Alexander D'yachenko

Main article: History of chemistry

The history of chemistry spans a period from very old times to the present. Since several millennia BC, civilizations were using technologies that would eventually form the basis of the various branches of chemistry. Examples include extracting metals from ores, making pottery and glazes, fermenting beer and wine, extracting chemicals from plants for medicine and perfume, rendering fat into soap, making glass, and making alloys like bronze. Chemistry was preceded by its protoscience, alchemy, which is an intuitive but non-scientific approach to understanding the constituents of matter and their interactions. It was unsuccessful in explaining the nature of matter and its transformations, but, by performing experiments and recording the results, alchemists set the stage for modern chemistry. Chemistry as a body of knowledge distinct from alchemy began to emerge when a clear differentiation was made between them by Robert Boyle in his work The Sceptical Chymist (1661). While both alchemy and chemistry are concerned with matter and its transformations, the crucial difference was given by the scientific method that chemists employed in their work. Chemistry is considered to have become an established science with the work of Antoine Lavoisier, who developed a law of conservation of mass that demanded careful measurement and quantitative observations of chemical phenomena. The history of chemistry is intertwined with the history of thermodynamics, especially through the work of Willard Gibbs.

The definition of chemistry has changed over time, as new discoveries and theories add to the functionality of the science. The term "chymistry", in the view of noted scientist Robert Boyle in 1661, meant the subject of the material principles of mixed bodies. In 1663, the chemist Christopher Glaser described "chymistry" as a scientific art, by which one learns to dissolve bodies, and draw from them the different substances on their composition, and how to unite them again, and exalt them to a higher perfection.

The 1730 definition of the word "chemistry", as used by Georg Ernst Stahl, meant the art of resolving mixed, compound, or aggregate bodies into their principles; and of composing such bodies from those principles. In 1837, Jean-Baptiste Dumas considered the word "chemistry" to refer to the science concerned with the laws and effects of molecular forces. This definition further evolved until, in 1947, it came to mean the science of substances: their structure, their properties, and the reactions that change them into other substances – a characterization accepted by Linus Pauling. More recently, in 1998, Professor Raymond Chang broadened the definition of "chemistry" to mean the study of matter and the changes it undergoes.

Main article: History of chemistry

See also: Alchemy and Timeline of chemistry

Democritus' atomist philosophy was later adopted by Epicurus (341–270 BCE).

Early civilizations, such as the Egyptians Babylonians and Indians amassed practical knowledge concerning the arts of metallurgy, pottery and dyes, but didn't develop a systematic theory.

A basic chemical hypothesis first emerged in Classical Greece with the theory of four elements as propounded definitively by Aristotle stating that fire, air, earth and water were the fundamental elements from which everything is formed as a combination. Greek atomism dates back to 440 BC, arising in works by philosophers such as Democritus and Epicurus. In 50 BCE, the Roman philosopher Lucretius expanded upon the theory in his book De rerum natura (On The Nature of Things). Unlike modern concepts of science, Greek atomism was purely philosophical in nature, with little concern for empirical observations and no concern for chemical experiments.

An early form of the idea of conservation of mass is the notion that "Nothing comes from nothing" in Ancient Greek philosophy, which can be found in Empedocles (approx. 4th century BC): "For it is impossible for anything to come to be from what is not, and it cannot be brought about or heard of that what is should be utterly destroyed." and Epicurus (3rd century BC), who, describing the nature of the Universe, wrote that "the totality of things was always such as it is now, and always will be".[47]

15th-century artistic impression of Jābir ibn Hayyān (Geber), a Perso-Arab alchemist and pioneer in organic chemistry.

In the Hellenistic world the art of alchemy first proliferated, mingling magic and occultism into the study of natural substances with the ultimate goal of transmuting elements into gold and discovering the elixir of eternal life. Work, particularly the development of distillation, continued in the early Byzantine period with the most famous practitioner being the 4th century Greek-Egyptian Zosimos of Panopolis. Alchemy continued to be developed and practised throughout the Arab world after the Muslim conquests, and from there, and from the Byzantine remnants, diffused into medieval and Renaissance Europe through Latin translations.

The development of the modern scientific method was slow and arduous, but an early scientific method for chemistry began emerging among early Muslim chemists, beginning with the 9th century Perso-Arab chemist Jābir ibn Hayyān, popularly known as "the father of chemistry". The Arabic works attributed to him introduced a systematic classification of chemical substances, and provided instructions for deriving an inorganic compound (sal ammoniac or ammonium chloride) from organic substances (such as plants, blood, and hair) by chemical means. Some Arabic Jabirian works (e.g., the "Book of Mercy", and the "Book of Seventy") were later translated into Latin under the Latinized name "Geber", and in 13th-century Europe an anonymous writer, usually referred to as pseudo-Geber, started to produce alchemical and metallurgical writings under this name. Later influential Muslim philosophers, such as Abū al-Rayhān al-Bīrūnī and Avicenna disputed the theories of alchemy, particularly the theory of the transmutation of metals.

Under the influence of the new empirical methods propounded by Sir Francis Bacon and others, a group of chemists at Oxford, Robert Boyle, Robert Hooke and John Mayow began to reshape the old alchemical traditions into a scientific discipline. Boyle in particular is regarded as the founding father of chemistry due to his most important work, the classic chemistry text The Sceptical Chymist where the differentiation is made between the claims of alchemy and the empirical scientific discoveries of the new chemistry. He formulated Boyle's law, rejected the classical "four elements" and proposed a mechanistic alternative of atoms and chemical reactions that could be subject to rigorous experiment.

Antoine-Laurent de Lavoisier is considered the "Father of Modern Chemistry".

The theory of phlogiston (a substance at the root of all combustion) was propounded by the German Georg Ernst Stahl in the early 18th century and was only overturned by the end of the century by the French chemist Antoine Lavoisier, the chemical analogue of Newton in physics; who did more than any other to establish the new science on proper theoretical footing, by elucidating the principle of conservation of mass and developing a new system of chemical nomenclature used to this day.

Before his work, though, many important discoveries had been made, specifically relating to the nature of 'air' which was discovered to be composed of many different gases. The Scottish chemist Joseph Black (the first experimental chemist) and the Flemish Jan Baptist van Helmont discovered carbon dioxide, or what Black called 'fixed air' in 1754; Henry Cavendish discovered hydrogen and elucidated its properties and Joseph Priestley and, independently, Carl Wilhelm Scheele isolated pure oxygen.

English scientist John Dalton proposed the modern theory of atoms; that all substances are composed of indivisible 'atoms' of matter and that different atoms have varying atomic weights.

The development of the electrochemical theory of chemical combinations occurred in the early 19th century as the result of the work of two scientists in particular, Jöns Jacob Berzelius and Humphry Davy, made possible by the prior invention of the voltaic pile by Alessandro Volta. Davy discovered nine new elements including the alkali metals by extracting them from their oxides with electric current.

In his periodic table, Dmitri Mendeleev predicted the existence of 7 new elements, and placed all 60 elements known at the time in their

British William Prout first proposed ordering all the elements by their atomic weight as all atoms had a weight that was an exact multiple of the atomic weight of hydrogen. J.A.R. Newlands devised an early table of elements, which was then developed into the modern periodic table of elements in the 1860s by Dmitri Mendeleev and independently by several other scientists including Julius Lothar Meyer. The inert gases, later called the noble gases were discovered by William Ramsay in collaboration with Lord Rayleigh at the end of the century, thereby filling in the basic structure of the table.

At the turn of the twentieth century the theoretical underpinnings of chemistry were finally understood due to a series of remarkable discoveries that succeeded in probing and discovering the very nature of the internal structure of atoms. In 1897, J.J. Thomson of Cambridge University discovered the electron and soon after the French scientist Becquerel as well as the couple Pierre and Marie Curie investigated the phenomenon of radioactivity. In a series of pioneering scattering experiments Ernest Rutherford at the University of Manchester discovered the internal structure of the atom and the existence of the proton, classified and explained the different types of radioactivity and successfully transmuted the first element by bombarding nitrogen with alpha particles.

His work on atomic structure was improved on by his students, the Danish physicist Niels Bohr and Henry Moseley. The electronic theory of chemical bonds and molecular orbitals was developed by the American scientists Linus Pauling and Gilbert N. Lewis.

The year 2011 was declared by the United Nations as the International Year of Chemistry. It was an initiative of the International Union of Pure and Applied Chemistry, and of the United Nations Educational, Scientific, and Cultural Organization and involves chemical societies, academics, and institutions worldwide and relied on individual initiatives to organize local and regional activities.

Organic chemistry was developed by Justus von Liebig and others, following Friedrich Wöhler's synthesis of urea which proved that living organisms were, in theory, reducible to chemistry. Other crucial 19th century advances were; an understanding of valence bonding (Edward Frankland in 1852) and the application of thermodynamics to chemistry (J. W. Gibbs and Svante Arrhenius in the 1870s).

Harald V (Norwegian pronunciation: [ˈhɑ̂rːɑɫ dɛn ˈfɛ̂mtə];[3] born 21 February 1937) is the King of Norway. He acceded to the throne on 17 January 1991.

Harald was the third child and only son of King Olav V and Princess Märtha of Sweden. He was second in the line of succession at the time of his birth, behind his father. In 1940, as a result of the German occupation during World War II, the royal family went into exile. Harald spent part of his childhood in Sweden and the United States. He returned to Norway in 1945, and subsequently studied for periods at the University of Oslo, the Norwegian Military Academy, and Balliol College, Oxford.

Following the death of his grandfather Haakon VII in 1957, Harald became crown prince as his father became king. A keen sportsman, he represented Norway in sailing at the 1964, 1968, and 1972 Olympic Games, and later became patron of World Sailing. Harald married Sonja Haraldsen in 1968, their relationship having initially been controversial due to her status as a commoner. The couple have two children, Märtha Louise and Haakon. Harald became king following his father's death in 1991, with Haakon becoming his heir apparent.

He is a great-grandson of King Edward VII of the United Kingdom and second cousin of Elizabeth II.

Prince Harald with his mother Crown Princess Märtha

Prince Harald was born at the Skaugum estate during the reign of his grandfather King Haakon VII and was baptised in the Royal Chapel of the Royal Palace in Oslo on 31 March 1937 by Bishop Johan Lunde. His godparents were: his paternal grandparents King Haakon VII and Queen Maud of Norway; his maternal grandparents Prince Carl and Princess Ingeborg of Sweden; King Leopold III of Belgium; Queen Mary and King George VI of the United Kingdom; and Crown Princess Ingrid of Denmark. His parents already had two daughters, Princess Ragnhild and Princess Astrid.

At the time of Harald's birth, he was 2nd in line of succession to the Norwegian throne following his father, Crown Prince Olav; and also was 16th in line of succession to the British throne as a descendant of King Edward VII through his paternal grandmother, Queen Maud.

In 1940 the entire royal family had to flee Oslo because of the German invasion. It was deemed safer for the family to split up. The King and Crown Prince Olav would remain in Norway and the Crown Princess was to make her way to Sweden with the three children. The latter party reached Sweden on the night of 10 April, but although Crown Princess Märtha was Swedish-born, they encountered problems at the border station. According to Princess Astrid and others who were present, they were admitted only after the driver threatened to ram the border gate. Another account does not describe the escape so dramatically.[4] However, when the King and Crown Prince inquired of Swedish foreign minister Christian Günther whether they could sleep one night in Sweden without being interned, their request was refused.[4]

Harald spent the following days in Sälen before moving to Prince Carl Bernadotte's home in Frötuna on 16 April. On 26 April the group moved to Drottningholm in Stockholm. King Gustaf V has been accounted to have had an amicable relationship with his Norwegian guests, but the topic of the war in Norway was not to be raised. However, influential Swedish politicians, including Minister of Justice Westman, wanted the Crown Princess and Prince Harald to be sent back to Norway so he could be proclaimed King by the Germans.[4][5] After the King and Crown Prince had to leave Norway on 7 June they felt Sweden might not be the best place for the rest of the family, and started planning for them to go to the United States. On 17 August the Crown Princess and her children left for the United States from Petsamo, Finland, aboard the United States Army transport ship American Legion.[4]

Harald and his mother and sisters lived in Washington, D.C. during the war,[6] while his father, Crown Prince Olav, and his grandfather, King Haakon, stayed in London with the Norwegian government-in-exile. One of the notable events he remembers from that time is standing behind Franklin D. Roosevelt when he was sworn in for his fourth term on the South Portico of the White House in 1945. Such childhood experiences are reflected in a trace of an American accent when he speaks English.[7] The Doris Kearns Goodwin book No Ordinary Time: Franklin and Eleanor Roosevelt and the Home Front in World War II contains a picture of the King (then Prince) playing with FDR's dog, Fala, on the North Lawn of the White House in 1944.

Harald visited Norwegian servicemen training in the United States. The prince also made visits outside America, travelling north to visit Norwegian personnel at the training base "Little Norway" in Ontario, Canada. He attended The White Hall Country School from 1943. Prince Harald returned to Norway with his family at the war's end in 1945.

In the autumn of 1945 he was enrolled in third grade of Smestad skole as the first member of the royal family to attend a public (state) school. Amidst this when he was only 17 years old in 1954, his mother died of cancer. The Crown Princess's death was a tremendous loss for him and his family as well as for Norway,[8] and he named his daughter Märtha to honour her memory. Four years later in 1958 he would lose his maternal grandmother Princess Ingeborg of Denmark.

Prince Harald as a student in the Cavalry Officers' Candidate School, Trandum

In 1955 he graduated from Oslo katedralskole and in the autumn of that year, Harald began studies at the University of Oslo. He later attended the Cavalry Officers' Candidate School at Trandum, followed by enrollment at the Norwegian Military Academy, from which he graduated in 1959. On 21 September 1957 at the death of his grandfather, Harald became crown prince at the age of 20 and he attended the Council of State for the first time six days later and took the oath to the Constitution of Norway on 21 February 1958. In the same year, he also served as regent in the King's absence for the first time.

Crown Prince Harald with Australian Prime Minister John Gorton in 1970.

In 1960, Harald entered Balliol College, Oxford where he studied history, economics and politics.[7] He was a keen rower during his student days at Oxford and was taught to row by fellow student and friend Nick Bevan, later a leading British school rowing coach. In 1960, he also made his first official journey abroad, visiting the United States in connection with the fiftieth anniversary of the American Scandinavian Foundation. An avid sailor,[9] Harald represented Norway in the yachting events of the Summer Olympics in Tokyo in 1964,[10] Mexico City in 1968,[7] and Munich in 1972. The Crown Prince carried the Norwegian flag at the opening parade of the 1964 Summer Olympics. Harald is an honorary president of the International Soling Association.

Harald married a commoner, Sonja Haraldsen, at Oslo Domkirke in Oslo on 29 August 1968. The pair had dated for nine years, but Olav was reluctant to allow his son to marry a commoner. Olav only relented when Harald told his father that if he was not allowed to marry Sonja he would not marry at all. This would have ended the reign of his family and the Norwegian monarchy, as Harald was the sole heir to the throne. The couple have two children, Princess Märtha Louise and Crown Prince Haakon, heir apparent to the Norwegian throne.

On the death of his father on 17 January 1991, Harald succeeded automatically to the Norwegian throne. He became the first Norwegian-born monarch since Olav IV died in 1387, a gap of 604 years. Harald is the sixth King of Norway to bear that name, and the first in 855 years. The five other kings who have borne the name are Harald Fairhair, Harald Greycloak, Harald Bluetooth, Harald Hardrada, and Harald Gille. Harald Bluetooth is usually not given a number in the Norwegian list of kings, therefore Harald is 'only' numbered as Harald V. King Harald made the decision to use his grandfather's royal motto, "Alt for Norge". The King also chose to continue the tradition of royal benediction, a tradition that had been introduced with his father, and was consecrated together with Queen Sonja in the Nidaros Cathedral on 23 June 1991.[11]

The reign of King Harald has been marked by modernization and reform for the Norwegian Royal family. The King has cooperated closely with Queen Sonja and the Crown Prince in making the royal household more open to the Norwegian public and the Norwegian media. King Harald's decision to accept two more commoners into the royal family, Crown Princess Mette-Marit and Ari Behn, has been interpreted as a sign of modernization and adjustment.[12][13] Under King Harald and Queen Sonja's leadership, comprehensive renovation projects on the Bygdøy Royal Estate, the Royal Palace, the royal stables and Oscarshall have also taken place. The latter three have also been opened to the public and tourists.[14] Together with Queen Sonja, the king has also for decades attempted to establish a palace museum in Oslo.[15][16]

While the Constitution vests the King with executive power, he is not politically responsible for exercising it. This is in accordance not only with provisions of the Constitution, but with conventions established since the definitive establishment of parliamentary rule in Norway in 1884. His acts are not valid without the countersignature of a member of the Council of State (cabinet)–usually the Prime Minister–and proceedings of the Council of State are signed by all of its members. Although he nominally has the power of veto, no Norwegian king has exercised it since the dissolution of the union with Sweden in 1905. Even then, the King's veto power is suspensive, not absolute as is the case with British monarchs. A royal veto can be overridden if the Storting passes the same bill following a general election.

While the Constitution nominally vests the King with the power to appoint the government, in practice the government must maintain the confidence of Parliament. The King appoints the leader of the parliamentary bloc with the majority as prime minister. When the parliamentary situation is unclear, the King relies on the advice of the President of Parliament and the sitting prime minister. Unlike some monarchs, Harald does not have the power to dissolve Parliament; the Constitution does not allow snap elections.

The King meets with the Council of State at the Royal Palace every Friday. He also has weekly meetings with the Prime Minister and the Minister of Foreign Affairs. He receives foreign envoys, and formally opens parliament every October delivering a speech from the throne during each opening. He travels extensively throughout Norway and makes official state visits to other countries, as well as receiving and hosting guests.

Until 2012, the King of Norway was, according to the constitution, the formal head of the Church of Norway. The constitutional amendment of 21 May 2012 made the King no longer the formal head, but he is still required to be of the Evangelical Lutheran religion.

On 8 May 2018, the King's constitutional status as holy was dissolved, while leaving his sovereign immunity intact.[17]

In 1994, both the King and Crown Prince Haakon played roles during the opening ceremony of the Lillehammer Olympics. The King opened the games, while the Crown Prince lit the cauldron, paying tribute to both the King and his grandfather as Olympians. The King has also represented Norway at opening ceremonies of Olympic Games, among them Torino and Beijing. However, he wasn't present in Vancouver; the Crown Prince attended instead, with the King and Queen attending later in the games.

With his sailing crew he won World Championship bronze, silver and gold medals, in 1988, 1982 and 1987, respectively. In July 2005, the King and his crew aboard the royal sailboat Fram XV won the gold medal at the European Championships in Sweden. In the 2007 World Championship the King came in sixth place.[18]

King Harald V in October 2021 at the opening of Sámi Parliament session of 2021-2022

King Harald's leadership during Norwegian national crises, such as the New Year's Day Storm, the landslide in Gjerdum and particularly the 2011 attacks, has been met with both national and international acclaim.[19][20][21][22]

In 2015, he became the world's first reigning monarch to visit Antarctica, specifically the Norwegian dependency Queen Maud Land.[23] In 2016, King Harald V competed with a team for the sailing World Championships on Lake Ontario, Toronto.[24] The king came second in the classic fleet category.[25] He was dubbed "Sailor-King" by Canada's National Post as he slept on board his yacht "Sira".[26]

In 2016 Harald, in a speech marking 25 years on the throne, sought to unify Norwegians coming from Afghanistan and Pakistan as well as “girls who love girls, boys who love boys and girls and boys who love each other.”[27]

Since the start of the twenty-first century King Harald has been unable to perform his duties as sovereign due to ill health on a few occasions: from December 2003 to mid-April 2004 due to urinary bladder cancer, from April to early June 2005 due to aortic stenosis, and in 2020 he was in hospital for cardiac surgery (replacement of a heart valve). Crown Prince Haakon served as the country's regent on these occasions, including giving the King's Speech at the State opening of parliament in 2020.

When the King and Queen turned 80 years old in 2017, the King decided to open the former royal stables to the public as a gift to his wife, the Queen. The new venue was named The Queen Sonja Art Stable and is the first institution owned by the royal family which is permanently open to the public.[28] King Harald was made Name of the Year by the newspaper VG in 2017.[29]

On 17 January 2021, King Harald celebrated 30 years on the throne of Norway.[30]

• 21 February 1937 – 21 September 1957: His Royal Highness Prince Harald of Norway
• 21 September 1957 – 17 January 1991: His Royal Highness The Crown Prince of Norway
• Since 17 January 1991: His Majesty The King of Norway

Royal coat of arms

Royal standard

Royal monogram

The King is a four-star general, an admiral, and formally the Supreme Commander of the Norwegian Armed Forces. The infantry battalion His Majesty the King's Guard are considered the King's and the Royal Family's bodyguards. They guard the Royal residences, including the Royal Palace, the Crown Prince Residence at Skaugum, and the Royal Mausoleum at Akershus Castle.

The King is Grand Master of the Royal Norwegian Order of St. Olav and the Royal Norwegian Order of Merit.

Norway – Grand Master of the Royal Norwegian Order of St Olav – Grand Cross with collar of the Royal Norwegian Order of St. Olav°

Norway – Grand Master of the Royal Norwegian Order of Merit – Grand Cross°

Norway – St Olav's medal°

Norway – Defence Service Medal with Laurel Branch°

Norway – Royal House Centennial Medal°

Norway – King Haakon VII Commemorative Medal 1. October 1957°

Norway – King Haakon VII 1905–1955 Jubilee Medal°

Norway – Haakon VIIs Centenary Medal°

Norway – Olav Vs Commemorative Medal of 30. January 1991°

Norway – Olav Vs Jubilee Medal°

Norway – Olav Vs Centenary Medal°

Norway – Defence Service Medal with three stars°

Norway – Army National Service Medal with three stars°

Norway – Krigsdeltakerforbundet Badge of Honour°

Norway – Norwegian Red Cross Badge of Honour°

Norway – Norwegian Reserve Officers Federal Badge of Honour°

Norway – The Naval Society Medal of Merit in gold°

Norway – Norwegian Shooting Society Badge of Honour°

Norway – The Norwegian Confederation of Sports Centenary Medal°

Norway – Norwegian Shooting Society Commemorative Medal in gold°

Norway – Oslo Military Society Badge of Honour in Gold°

In the British Army, Harald V was the final Colonel-in-Chief of the Green Howards.[31] He is also an honorary Colonel in the British Royal Marines.[32] He is patron of the Anglo-Norse Society in London, together with Queen Elizabeth II, his second cousin. Harald is in the line of succession to the British throne, because of his descent from King Edward VII of the United Kingdom. He is a Stranger Knight of the Garter, an Honorary Knight Grand Cross of the Royal Victorian Order, and a Recipient of the Royal Victorian Chain, as well as numerous other orders of chivalry.

Iceland – Grand Cross with Collar of the Order of the Falcon °

Sweden – Knight with Collar of the Order of the Seraphim °

Sweden – Gustaf Vs 90th Anniversary Medal °

Sweden – HM King Carl XVI Gustaf 50th Anniversary Medal

Denmark – Knight with Collar of the Order of the Elephant °

Denmark – Grand Commander of the Order of the Dannebrog °

Finland – Commander Grand Cross with Collar of the Order of the White Rose of Finland °

Estonia – Collar of the Order of the Cross of Terra Mariana °

Estonia – Collar of the Order of the White Star

Latvia – Commander Grand Cross with Chain of the Order of the Three Stars °

Latvia – Grand Cross of the Order of Viesturs °

Lithuania – Grand Cross (1998) with Golden Chain (2011) of the Order of Vytautas the Great °[33]

United Kingdom – Recipient of the Royal Victorian Chain (1994) °

United Kingdom – Honorary Knight Grand Cross of the Royal Victorian Order (1955) °

United Kingdom – Stranger Knight of the Order of the Garter (990th member; 2001) °

United Kingdom – Honorary Freedom of Newcastle upon Tyne[34][35] (November 2008)

Argentina – Collar of the Order of the Liberator General San Martín

Austria – Grand Star of the Decoration of Honour for Services to the Republic of Austria (1964) °[36]

Belgium – Grand Cordon of the Order of Leopold °

Brazil – Grand Collar of the Order of the Southern Cross °

Bulgaria – Grand Cross of the Order of Stara Planina °

Chile – Collar of the Order of the Merit °

Croatia – Grand Order of King Tomislav °

France – Grand Cross of the Légion d'honneur °

Germany – Grand Cross Special Class of the Order of Merit of the Federal Republic of Germany °

Greece – Grand Cross of the Order of the Redeemer °

Greece – The Royal House of Greece Centenary Medal °

Hungary – Grand Cross with Collar of the Order of Merit of the Republic of Hungary °

Olympic flag.svg IOC – The Golden Olympic order °

Italy – Knight Grand Cross (06/1965) with Collar (10/2001) of the Order of Merit of the Italian Republic °[37]

Japan – Grand Cordon with Collar of the Order of the Chrysanthemum °

Jordan – Grand Cross with Collar of the Order of al-Hussein bin Ali °

Yugoslavia – Order of the Yugoslav Great Star °

Luxembourg – Grand Cross of the Order of Adolph of Nassau °

Luxembourg – Knight of the Order of the Gold Lion of the House of Nassau°

Luxembourg – Medal to commemorate the wedding of Grand Duke Jean and Grand Duchess Joséphine-Charlotte °

Netherlands – Knight Grand Cross of the Order of the Netherlands Lion °

Netherlands – Grand Cross of the Order of the Crown °

Netherlands – Commander of the Order of the Golden Ark °

Netherlands – Medal to commemorate the enthronement of Queen Beatrix °

Poland – Knight Grand Cross of the Order of the White Eagle °

Portugal – Grand Cross of the Military Order of Aviz (05/11/1980) °[38]

Portugal – Grand Collar of the Order of Infante Dom Henrique (13 February 2004) °[38]

Portugal – Grand Collar of the Order of St. James of the Sword (26 May 2008) °[38]

Romania – Sash Rank of the Order of the Star of Romania °

Slovakia – Grand Cross (or 1st Class) of the Order of the White Double Cross (2010) °[39]

Slovenia: Recipient of the Decoration for Exceptional Merits (2011) °

Spain – 1,192nd Knight and Collar of the Order of the Golden Fleece (21 April 1995) °[40]

Spain – Knight Grand Cross of the Order of Charles III (12/04/1982) °[41]

Spain – Collar of the Order of Charles III (30 June 2006) °[42]

South Africa – Grand Cross of the Order of Good Hope °

South Korea – Recipient of the Grand Order of Mugunghwa °

Thailand – Knight of the Order of the Royal House of Chakri (19 September 1960)°[43]

Thailand – Knight Grand Cordon (Special Class) of the Order of Chula Chom Klao °

Turkey – First Class of the Order of the State of Republic of Turkey °

The mark ° shows honours mentioned on his official website page about decorations

Harald V received an honorary degree of Doctor of Civil Law from Oxford University in 2006 (as did his father, King Olav, in 1937, and his grandfather, King Haakon, in 1943).[44] The King also received honorary doctorates from Heriot-Watt University in Scotland in 1994,[45] the University of Strathclyde in Scotland in 1985, Waseda University in Japan in 2001, and Pacific Lutheran University in Tacoma, Washington, in 2015.[46] He is also an honorary fellow at Balliol College, Oxford.

• Ireland – Freedom of the City of Cork.
• Spirit of Luther Award, awarded by Luther College of Decorah, IA
• A 230,000 km2 area in Antarctica is named Prince Harald Coast in his honour.
• In 2007 King Harald was awarded the Holmenkollen medal with Simon Ammann, Frode Estil, Odd-Bjørn Hjelmeset, and his wife Queen Sonja.
• Portugal – Key of Honor to the City of Lisbon, on 28 May 2008[47]
• In 2013, a 6,500 km2 area in Svalbard was named Harald V Land.[48]

King Harald is closely related to other European monarchs. He is the first cousin once removed of King Philippe of Belgium and Grand Duke Henri of Luxembourg, the second cousin of Queen Margrethe II of Denmark, Queen Anne-Marie of Greece (double second cousins and double third cousins) and Queen Elizabeth II of the United Kingdom, and the second cousin once removed of King Carl XVI Gustaf of Sweden.

1. Coronation requirement discarded by constitutional amendment in 1908. Harald V swore the Royal Oath in the Storting on 21 January 1991 and received the benediction in the Nidaros Cathedral on 23 June 1991.
2. "The Royal Family". Retrieved 25 October 2014.
3. Berulfsen, Bjarne (1969). Norsk Uttaleordbok (in Norwegian). Oslo: H. Aschehoug & Co (W Nygaard). pp. 64, 91, 129.
4. Hegge, Per Egil; Harald V, En biografi; N.W. Damm & Søn AS; 2006.
5. "Kidnapper Foiled?". Time. 2 September 1940. Archived from the original on 2 February 2009. Retrieved 17 January 2009.
6. "Non-Political Campaign". Time Magazine. 9 September 1940. p. 2. Archived from the original on 3 February 2009. Retrieved 17 January 2009.
7. "Those Apprentice Kings and Queens Who May – One Day – Ascend a Throne," New York Times. 14 November 1971.
8. "Crown Princess Märtha (1901-1954)". Norwegian Royal House. Archived from the original on 16 June 2018. Retrieved 7 November 2018.
9. "Victory by Design". Time Magazine. 27 September 1963. p. 1. Archived from the original on 22 December 2008. Retrieved 17 January 2009.
10. "HP-Time.com". Time Magazine. 26 June 1964. p. 2. Archived from the original on 3 February 2009. Retrieved 17 January 2009.
11. "The Consecration of King Harald and Queen Sonja". www.kongehuset.no (in Norwegian). Archived from the original on 28 December 2017. Retrieved 28 December 2017.
12. NRK. "– Å si at vi ikke er åpne, er rett og slett feil". NRK (in Norwegian Bokmål). Retrieved 29 December 2017.
13. "Stanghelle: "Kong Harald står frem som mannen som forstår sin egen tid"". Aftenposten. Archived from the original on 29 December 2017. Retrieved 28 December 2017.
14. "The Royal Palace is open to the public". www.royalcourt.no. Archived from the original on 29 December 2017. Retrieved 28 December 2017.
15. Totl, Kjell Arne. "Kongehusekspert Kjell Arne Totland skriver: Gi kongeparet et permanent slottsmuseum". Aftenposten (in Norwegian Bokmål). Retrieved 27 December 2018.[permanent dead link]
16. Moxnes, Agnes (27 December 2018). "På tide med et slottsmuseum". NRK (in Norwegian Bokmål). Retrieved 27 December 2018.
17. NTB 2018. 'Fra tirsdag er ikke kongen lenger hellig'. NRK, 7 May. Retrieved on 8 May. https://www.nrk.no/norge/fra-tirsdag-er-ikke-kongen-lenger-hellig-1.14039929
18. Sandefjords Blad on the King's performance in the World Championship (in Norwegian) Retrieved 10 September 2007.[dead link]
19. Erlanger, Steven (15 October 2011). "King Harald of Norway Proves Mettle With Response to July 22 Deaths". The New York Times. ISSN 0362-4331. Retrieved 24 January 2018.
20. Rising, Malin (21 August 2011). "Norway remembers 77 killed in massacre". MSNBC. Retrieved 24 January 2018.
21. "Kongen om terrorangrepet: - Våre tanker går til ofrene". VG (in Norwegian). Archived from the original on 25 January 2018. Retrieved 24 January 2018.
22. Nyfløt, Hilda (21 August 2011). "- Hans aller beste tale". Dagbladet (in Norwegian). Retrieved 24 January 2018.
23. "King Harald visits Antarctic namesake". The Local. 11 February 2015. Archived from the original on 15 February 2015. Retrieved 15 February 2015.
24. "Sun shines for king in Antarctica". newsinenglish.no. 11 February 2015. Archived from the original on 14 February 2015. Retrieved 15 February 2015.
25. "King Harald begins Antarctic visit". The Norway Post. NRK/Aftenposten. 11 February 2015. Archived from the original on 15 February 2015. Retrieved 15 February 2015.
26. "King Harald of Norway in Canada to participate in sailing World Championships – Royal Central". royalcentral.co.uk. Archived from the original on 29 May 2017. Retrieved 30 May 2017.
27. "North American Eight Metre Association" (PDF). Archived from the original (PDF) on 8 August 2017.
28. "Norway's sailor king: Why Harald V has been sleeping on a yacht moored on Toronto's waterfront". National Post. Retrieved 30 May 2017.[dead link]
29. "The king's speech struck a chord".
30. "The Art Stable is open". www.royalcourt.no. Archived from the original on 29 December 2017. Retrieved 28 December 2017.
31. "Kongebiograf: Kong Harald blir mer populær jo eldre han blir" (in Norwegian). Archived from the original on 21 February 2018. Retrieved 21 February 2018.
32. "King and Queen for 30 years".
33. "No. 52834". The London Gazette (Supplement). 14 February 1992. p. 2582.
34. "No. 48634". The London Gazette (Supplement). 9 June 1981. p. 7795.
35. Lithuanian Presidency Archived 19 April 2014 at the Wayback Machine, Lithuanian Orders searching form
36. "King of Norway awarded Honorary Freedom of Newcastle". Norwegian Ministry of Foreign Affairs. Archived from the original on 12 February 2009. Retrieved 18 December 2008.
37. Solholm, Rolleiv (14 November 2008). "King Harald receives honorary title". Norwegian Broadcasting Corporation. Norway Post. Retrieved 14 November 2008.[dead link]
38. "Reply to a parliamentary question" (PDF) (in German). p. 170. Retrieved 8 October 2012.
39. Italian Presidency website, decorations – Harald V : Grand Cross – Collar
40. Portuguese presidential website, Orders search form
41. Slovak republic website, State honours Archived 13 April 2016 at the Wayback Machine : 1st Class received in 2010 (click on "Holders of the Order of the 1st Class White Double Cross" to see the holders' table)
42. Boletín Oficial del Estado
43. "Boletín Oficial del Estado" (PDF). Archived from the original (PDF) on 22 January 2015. Retrieved 16 July 2013.
44. Boletín Oficial del Estado
45. Royal Thai Government Gazette (28 December 1960). แจ้งความสำนักนายกรัฐมนตรี เรื่อง พระราชทานเครื่องราชอิสริยาภรณ์ (PDF) (in Thai). Retrieved 8 May 2019.
46. Article in VG on the honorary doctorate (in Norwegian)
47. webperson@hw.ac.uk. "Heriot-Watt University Edinburgh: Honorary Graduates". www1.hw.ac.uk. Retrieved 4 April 2016.
48. https://www.plu.edu/president/wp-content/uploads/sites/39/2019/09/honorary-doctorate-history-09-18-19.pdf
49. "State Visit continues". The Royal House of Norway. Archived from the original on 16 March 2014. Retrieved 16 March 2014.
50. "New land area named after King Harald". The Norway Post. NRK. 23 September 2013. Retrieved 11 October 2013.

It is native to stony and sandy plains in the Mojave Desert of California and the Sonoran Deserts of the Southwestern United States northwestern Mexico. It is and is very common in the northern, eastern, and southern parts of the desert.

Monoptilon bellioides is a short annual plant; in seasons with very little rainfall, the plant may only grow to 1–2 cm, if it grows at all, while in seasons of heavy rainfall, it can grow up to 25 cm tall. The leaves are linear, 5–10 mm long, with a blunt apex.

The flowers are produced in dense inflorescences (capitula), 2 cm diameter, with white ray florets and yellow disc florets in the center. The flowers open in the morning and close in the evening.

1. USDA, NRCS (n.d.). "Monoptilon bellioides". The PLANTS Database (plants.usda.gov). Greensboro, North Carolina: National Plant Data Team. Retrieved 13 July 2015.
2. Mojave Desert Wildflowers, Jon Mark Stewart, 1998, pg. 41
3. The Audubon Society Field Guide to North American Wildflowers, Western Region, 1992, pg. 380.

Heck reactionHeck reaction

Kumada couplingKumada coupling

Negishi couplingNegishi coupling

Sonogashira couplingSonogashira coupling

Stille reactionStille reaction

See also

Suzuki reactionSuzuki reaction

Negishi couplingNegishi coupling

Stille reactionStille reaction

Suzuki reactionSuzuki reaction

Sonogashira couplingSonogashira coupling

1. Drahl, Carmen (May 17, 2010). "In Names, History And Legacy". Chem. Eng. News. 88 (22): 31–33. doi:10.1021/cen-v088n020.p031. Retrieved June 4, 2011.
2. Heck, R. F. (1982). "Palladium-catalyzed vinylation of organic halides". Organic Reactions. Org. React. Vol. 27. pp. 345–390. doi:10.1002/0471264180.or027.02. ISBN 978-0471264187.
3. de Meijere, A.; Meyer, F. E. (1994). "Fine Feathers Make Fine Birds: The Heck Reaction in Modern Garb". Angew. Chem. Int. Ed. Engl. 33 (2324): 2379–2411. doi:10.1002/anie.199423791.
4. Beletskaya, I. P.; Cheprakov, A. V. (2000). "The Heck Reaction as a Sharpening Stone of Palladium Catalysis". Chem. Rev. 100 (8): 3009–3066. doi:10.1021/cr9903048. PMID 11749313.
5. Mc Cartney, Dennis; Guiry, Patrick J. (2011). "The asymmetric Heck and related reactions". Chem. Soc. Rev. 40 (10): 5122–5150. doi:10.1039/C1CS15101K. PMID 21677934.
6. Moritani, Ichiro; Fujiwara, Yuzo (1967). "Aromatic substitution of styrene-palladium chloride complex". Tetrahedron Lett. 8 (12): 1119–1122. doi:10.1016/S0040-4039(00)90648-8.
7. Fujiwara, Yuzo; Noritani, Ichiro; Danno, Sadao; Asano, Ryuzo; Teranishi, Shiichiro (1969). "Aromatic substitution of olefins. VI. Arylation of olefins with palladium(II) acetate". J. Am. Chem. Soc. 91 (25): 7166–9. doi:10.1021/ja01053a047. PMID 27462934.
8. Richard F. Heck (1969). "Mechanism of Arylation and Carbomethoxylation of Olefins with Organopalladium Compounds". J. Am. Chem. Soc. 91 (24): 6707–6714. doi:10.1021/ja01052a029.
9. Heck, R. F.; Nolley, J. P. (1972). "Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides". J. Org. Chem. 37 (14): 2320–2322. doi:10.1021/jo00979a024.
10. Mizoroki, T.; Mori, K.; Ozaki, A. (1971). "Arylation of Olefin with Aryl Iodide Catalyzed by Palladium". Bull. Chem. Soc. Jpn. 44 (2): 581. doi:10.1246/bcsj.44.581.
11. Dieck, H. A.; Heck, R. F. (1974). "Organophosphinepalladium complexes as catalysts for vinylic hydrogen substitution reactions". J. Am. Chem. Soc. 96 (4): 1133. doi:10.1021/ja00811a029.
12. Littke, A. F.; Fu, G. C. (2005). "Heck reactions of aryl chlorides catalyzed by palladium/tri-tert-butylphosphine: (E)-2-Methyl-3-phenylacrylic acid butyl ester and (E)-4-(2-phenylethenyl)benzonitrile". Organic Syntheses. 81: 63.
13. Ozawa, F.; Kubo, A.; Hayashi, T. (1992). "Generation of Tertiary Phosphine-Coordinated Pd(0) Species from Pd(OAc)2 in the Catalytic Heck Reaction". Chemistry Letters. 21 (11): 2177–2180. doi:10.1246/cl.1992.2177.
14. Bradshaw, Michael; Zou, Jianli; Byrne, Lindsay; Swaminathan Iyer, K.; Stewart, Scott G.; Raston, Colin L. (2011). "Pd(II) conjugated chitosan nanofibre mats for application in Heck cross-coupling reactions". Chem. Commun. 47 (45): 12292–12294. doi:10.1039/C1CC14717J. PMID 22011792.
15. De Vries; Johannes G. (2001). "The Heck reaction in the production of fine chemicals". Can. J. Chem. 79 (5–6): 1086. doi:10.1139/cjc-79-5-6-1086.
16. Hagiwara, Hisahiro; Sugawara, Yoshitaka; Hoshi, Takashi; Suzuki, Toshio (2005). "Sustainable Mizoroki–Heck reaction in water: remarkably high activity of Pd(OAc)2 immobilized on reversed phase silica gel with the aid of an ionic liquid". Chem. Commun. (23): 2942–2944. doi:10.1039/b502528a. PMID 15957033.
17. Lorand Kiss; Tibor Kurtan; Sandor Antus; Henri Brunner (2003). "Further insight into the mechanism of Heck oxyarylation in the presence of chiral ligands". Arkivoc: GB–653J.
18. Mitsuru Kitamura; Daisuke Kudo; Koichi Narasaka (2005). "Palladium(0)-catalyzed synthesis of pyridines from β-acetoxy-γ,δ-unsaturated ketone oximes". Arkivoc: JC–1563E.

1. Stephens, R. D.; Castro, C. E. (1963). "The Substitution of Aryl Iodides with Cuprous Acetylides. A Synthesis of Tolanes and Heterocyclics". J. Org. Chem. 28 (12): 3313–3315. doi:10.1021/jo01047a008.
2. Owsley, D. C.; Castro, C. E. (1972). "Substitution of Aryl Halides with Copper(I) Acetylides: 2-Phenylfuro[3,2-b]pyridine". Organic Syntheses. 52: 128. doi:10.15227/orgsyn.052.0128.; Collective Volume, vol. 6, p. 916
3. Rosenmund, Karl W.; Struck, Erich (1919). "Das am Ringkohlenstoff gebundene Halogen und sein Ersatz durch andere Substituenten. I. Mitteilung: Ersatz des Halogens durch die Carboxylgruppe" [The halogen bound to the ring carbon and its replacement by other substituents. I. Notice: Replacement of the halogen by the carboxyl group]. Ber. Dtsch. Chem. Ges. A/B (in German). 52 (8): 1749–1756. doi:10.1002/cber.19190520840.
4. von Braun, Julius; Manz, Gottfried (1931). "Fluoranthen und seine Derivate. III. Mitteilung" [Fluoranthene and its derivatives. III. Notification]. Justus Liebigs Ann. Chem. (in German). 488 (1): 111–126. doi:10.1002/jlac.19314880107.
5. Sonogashira, Kenkichi; Tohda, Yasuo; Hagihara, Nobue (1975). "A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines". Tetrahedron Lett. 16 (50): 4467–4470. doi:10.1016/s0040-4039(00)91094-3.
6. Sonogashira, Kenkichi (2002). "Development of Pd-Cu catalyzed cross-coupling of terminal acetylenes with sp2-carbon halides". J. Organomet. Chem. 653 (1–2): 46–49. doi:10.1016/s0022-328x(02)01158-0.
7. Batu, Gunes; Stevenson, Robert (1980). "Synthesis of natural isocoumarins, artemidin and 3-propylisocoumarin". J. Org. Chem. 45 (8): 1532–1534. doi:10.1021/jo01296a044.
8. Castro, Charles E.; Havlin, R.; Honwad, V. K.; Malte, A. M.; Moje, Steve W. (1969). "Copper(I) Substitutions. Scope and Mechanism of Cuprous Acetylide Substitutions". J. Am. Chem. Soc. 91 (23): 6464–6470. doi:10.1021/ja01051a049.

Castro-Stephens couplingCastro-Stephens coupling

Heck reactionHeck reaction

Stille reactionStille reaction

Suzuki reactionSuzuki reaction

Negishi couplingNegishi coupling

Kumada couplingKumada coupling

TransmetalationTransmetalation

It has the general form:

M1–R + M2–R′ → M1–R′ + M2–R

where R and R′ can be, but are not limited to, an alkyl, aryl, alkynyl, allyl, halogen, or pseudohalogen group. The reaction is usually an irreversible process due to thermodynamic and kinetic reasons. Thermodynamics will favor the reaction based on the electronegativities of the metals and kinetics will favor the reaction if there are empty orbitals on both metals.[1] There are different types of transmetalation including redox-transmetalation and redox-transmetalation/ligand exchange. During transmetalation the metal-carbon bond is activated, leading to the formation of new metal-carbon bonds.[2] Transmetalation is commonly used in catalysis, synthesis of main group complexes, and synthesis of transition metal complexes.

There are two main types of transmetalation, redox-transmetalation (RT) and redox-transmetalation/ligand-exchange (RTLE). Below, M1 is usually a 4d or 5d transition metal and M2 is usually a main group or 3d transition metal. By looking at the electronegativities of the metals and ligands, one can predict whether the RT or RTLE reaction will proceed and what products the reaction will yield. For example, one can predict that the addition of 3 HgPh2 to 2 Al will yield 3 Hg and 2 AlPh3 because Hg is a more electronegative element than Al.

M1n+–R + M2 → M1 + M2n+–R.

In redox-transmetalation a ligand is transferred from one metal to the other through an intermolecular mechanism. During the reaction one of the metal centers is oxidized and the other is reduced. The electronegativities of the metals and ligands is what causes the reaction to go forward. If M1 is more electronegative than M2, it is thermodynamically favorable for the R group to coordinate to the less electronegative M2.

M1–R + M2–X → M1–X + M2–R.

In redox-transmetalation/ligand exchange the ligands of two metal complexes switch places with each other, bonding with the other metal center. The R ligand can be an alkyl, aryl, alkynyl, or allyl group and the X ligand can be a halogen, pseudo-halogen, alkyl, or aryl group. The reaction can proceed by two possible intermediate steps. The first is an associative intermediate, where the R and X ligands bridge the two metals, stabilizing the transition state. The second and less common intermediate is the formation of a cation where R is bridging the two metals and X is anionic. The RTLE reaction proceeds in a concerted manner. Like in RT reactions, the reaction is driven by electronegativity values. The X ligand is attracted to highly electropositive metals. If M1 is a more electropositive metal than M2, it is thermodynamically favorable for the exchange of the R and X ligands to occur.

Transmetalation is often used as a step in the catalytic cycles of cross-coupling reactions. Some of the cross-coupling reactions that include a transmetalation step are Stille cross-coupling, Suzuki cross-coupling, Sonogashira cross-coupling, and Negishi cross-coupling. The most useful cross-coupling catalysts tend to be ones that contain palladium. Cross-coupling reactions have the general form of R′–X + M–R → R′–R + M–X and are used to form C–C bonds. R and R′ can be any carbon fragment. The identity of the metal, M, depends on which cross-coupling reaction is being used. Stille reactions use tin, Suzuki reactions use boron, Sonogashira reactions use copper, and Negishi reactions use zinc. The transmetalation step in palladium catalyzed reactions involve the addition of an R–M compound to produce an R′–Pd–R compound. Cross-coupling reactions have a wide range of applications in synthetic chemistry including the area of medicinal chemistry. The Stille reaction has been used to make an antitumor agent, (±)-epi-jatrophone;[3] the Suzuki reaction has been used to make an antitumor agent, oximidine II;[4] the Sonogashira reaction has been used to make an anticancer drug, eniluracil;[5] and the Negishi reaction has been used to make the carotenoid β-carotene via a transmetalation cascade.[6]

Lanthanide organometallic complexes have been synthesized by RT and RTLE. Lanthanides are very electropositive elements.

Organomercurials, such as HgPh2, are common kinetically inert RT and RTLE reagents that allow functionalized derivatives to be synthesized, unlike organolithiums and Grignard reagents.[7] Diarylmercurials are often used to synthesize lanthanide organometallic complexes. Hg(C6F5)2 is a better RT reagent to use with lanthanides than HgPh2 because it does not require a step to activate the metal.[8] However, phenyl-substituted lanthanide complexes are more thermally stable than the pentafluorophenyl complexes. The use of HgPh2 led to the synthesis of a ytterbium complex with different oxidation states on the two Yb atoms:[9]

Yb(C10H8)(THF)2 + HgPh2 → YbIIYbIIIPh5(THF)4

In the Ln(C6F5)2 complexes, where Ln = Yb, Eu, or Sm, the Ln–C bonds are very reactive, making them useful in RTLE reactions. Protic substrates have been used as a reactant with the Ln(C6F5)2 complex as shown: Ln(C6F5)2 + 2LH → Ln(L)2 + 2C6F5H. It is possible to avoid the challenges of working with the unstable Ln(C6F5)2 complex by forming it in situ by the following reaction:

Ln + HgR2 + 2 LH → Ln(L)2 + Hg + 2 RH

Organotins are also kinetically inert RT and RTLE reagents that have been used in a variety of organometallic reactions. They have applications to the synthesis of lanthanide complexes, such as in the following reaction:[10]

Yb + Sn(N(SiMe3)2)2 → Yb(N(SiMe3)2)2 + Sn

RT can be used to synthesize actinide complexes. RT has been used to synthesize uranium halides using uranium metal and mercury halides as shown:

U + HgX → UX + Hg (X = Cl, Br, I)[11]

This actinide RT reaction can be done with multiple mercury compounds to coordinate ligands other than halogens to the metal:

2 U + 3 (C5H5)2Hg + HgCl2 → 2 (C5H5)3UCl + 4 Hg

Alkaline earth metal complexes have been synthesized by RTLE, employing the same methodology used in synthesizing lanthanide complexes. The use of diphenylmercury in alkaline-earth metal reactions leads to the production of elemental mercury. The handling and disposal of elemental mercury is challenging due to its toxicity to humans and the environment. This led to the desire for an alternative RTLE reagent that would be less toxic and still very effective. Triphenylbismuth, BiPh3, was discovered to be a suitable alternative.[12] Mercury and bismuth have similar electronegativity values and behave similarly in RTLE reactions. BiPh3 has been used to synthesize alkaline-earth metal amides and alkaline-earth metal cyclopentadienides. The difference between HgPh2 and BiPh3 in these syntheses was that the reaction time was longer when using BiPh3.

1. Spessard, Gary O.; Miessler, Gary L. (2010). Organometallic Chemistry. New York, NY: Oxford University Press. ISBN 978-0195330991.
2. Osakada, Kohtaro (2003). Fundamentals of Molecular Catalysis. Amsterdam: Elsevier. ISBN 0444509216.
3. Gyorkos, Albert C.; Stille, John K.; Hegedus, Louis S. (1990). "The total synthesis of (±)-epi-jatrophone and (±)-jatrophone using palladium-catalyzed carbonylative coupling of vinyl triflates with vinyl stannanes as the macrocycle-forming step". J. Am. Chem. Soc. 112 (23): 8465–8472. doi:10.1021/ja00179a035.
4. Molander, Gary A.; Dehmel, Florian (2004). "Formal Total Synthesis of Oximidine II via a Suzuki-Type Cross-Coupling Macrocyclization Employing Potassium Organotrifluoroborates". J. Am. Chem. Soc. 126 (33): 10313–10318. doi:10.1021/ja047190o. PMID 15315445.
5. Cooke, Jason W. B.; Bright, Robert; Coleman, Mark J.; Jenkins, Kevin P. (2001). "Process Research and Development of a Dihydropyrimidine Dehydrogenase Inactivator: Large-Scale Preparation of Eniluracil Using a Sonogashira Coupling". Org. Process Res. Dev. 5 (4): 383–386. doi:10.1021/op0100100.
6. Zeng, Fanxing; Negishi, Ei-Ichi (2001). "A Novel, Selective, and Efficient Route to Carotenoids and Related Natural Products via Zr-Catalyzed Carboalumination and Pd- and Zn-Catalyzed Cross Coupling". Org. Lett. 3 (5): 719–722. doi:10.1021/ol000384y. PMID 11259045.
7. Vicente, José; Arcas, Aurelia; Gálvez López, María Dolores; Jones, Peter G. (2004). "Bis(2,6-dinitroaryl)platinum Complexes. 1. Synthesis through Transmetalation Reactions". Organometallics . 23 (14): 3521–3527. doi:10.1021/om049801r.
8. Deacon, Glen B.; Forsyth, Craig M.; Nickel, Siegbert (2002). "Bis(pentafluorophenyl)mercury—a versatile synthon in organo-, organooxo-, and organoamido-lanthanoid chemistry". J. Organomet. Chem. 647 (1–2): 50–60. doi:10.1016/S0022-328X(01)01433-4.
9. Bochkarev, Mikhail N.; Khramenkov, Vladimir V.; Radkov, Yury F.; Zakharov, Lev N.; Struchkov, Yury T. (1992). "Synthesis and characterization of pentaphenyldiytterbium Ph2Yb(THF)(μ-Ph)3Yb(THF)3". J. Organomet. Chem. 429: 27–39. doi:10.1016/0022-328X(92)83316-A.
10. Cetinkaya, Bekir; Hitchcock, Peter B.; Lappert, Michael F.; Smith, Richard G. (1992). "The first neutral, mononuclear 4f metal thiolates and new methods for corresponding aryl oxides and bis(trimethylsilyl)amides". J. Chem. Soc., Chem. Commun. 13 (13): 932–934. doi:10.1039/C39920000932.
11. Deacon, G.B.; Tuong, T.D. (1988). "A simple redox transmetallation synthesis of uranium tetrachloride and related preparations of uranium triiodide and chlorotris(cyclopentadienyl)uranium(IV)". Polyhedron. 7 (3): 249–250. doi:10.1016/S0277-5387(00)80561-6.
12. Gillett-Kunnath, Miriam M.; MacLellan, Jonathan G.; Forsyth, Craig M.; Andrews, Philip C.; Deacon, Glen B.; Ruhlandt-Senge, Karin (2008). "BiPh3—A convenient synthon for heavy alkaline-earth metal amides". Chem. Commun. 37 (37): 4490–4492. doi:10.1039/b806948d. PMID 18802600.

The procedure uses transition metal catalysts, typically nickel or palladium, to couple a combination of two alkyl, aryl or vinyl groups. The groups of Robert Corriu and Makoto Kumada reported the reaction independently in 1972.[1][2]

The reaction is notable for being among the first reported catalytic cross-coupling methods. Despite the subsequent development of alternative reactions (Suzuki, Sonogashira, Stille, Hiyama, Negishi), the Kumada coupling continues to be employed in many synthetic applications, including the industrial-scale production of aliskiren, a hypertension medication, and polythiophenes, useful in organic electronic devices.

The first investigations into the catalytic coupling of Grignard reagents with organic halides date back to the 1941 study of cobalt catalysts by Morris S. Kharasch and E. K. Fields.[3] In 1971, Tamura and Kochi elaborated on this work in a series of publications demonstrating the viability of catalysts based on silver,[4] copper[5] and iron.[6] However, these early approaches produced poor yields due to substantial formation of homocoupling products, where two identical species are coupled.

These efforts culminated in 1972, when the Corriu and Kumada groups concurrently reported the use of nickel-containing catalysts. With the introduction of palladium catalysts in 1975 by the Murahashi group, the scope of the reaction was further broadened.[7] Subsequently, many additional coupling techniques have been developed, culminating in the 2010 Nobel Prize in Chemistry recognized Ei-ichi Negishi, Akira Suzuki and Richard F. Heck for their contributions to the field.

According to the widely accepted mechanism, the palladium-catalyzed Kumada coupling is understood to be analogous to palladium's role in other cross coupling reactions. The proposed catalytic cycle involves both palladium(0) and palladium(II) oxidation states. Initially, the electron-rich Pd(0) catalyst (1) inserts into the R–X bond of the organic halide. This oxidative addition forms an organo-Pd(II)-complex (2). Subsequent transmetalation with the Grignard reagent forms a hetero-organometallic complex (3). Before the next step, isomerization is necessary to bring the organic ligands next to each other into mutually cis positions. Finally, reductive elimination of (4) forms a carbon–carbon bond and releases the cross coupled product while regenerating the Pd(0) catalyst (1).[8] For palladium catalysts, the frequently rate-determining oxidative addition occurs more slowly than with nickel catalyst systems.[8]

Current understanding of the mechanism for the nickel-catalyzed coupling is limited. Indeed, the reaction mechanism is believed to proceed differently under different reaction conditions and when using different nickel ligands.[9] In general the mechanism can still be described as analogous to the palladium scheme (right). Under certain reaction conditions, however, the mechanism fails to explain all observations. Examination by Vicic and coworkers using tridentate terpyridine ligand identified intermediates of a Ni(II)-Ni(I)-Ni(III) catalytic cycle,[10] suggesting a more complicated scheme. Additionally, with the addition of butadiene, the reaction is believed to involve a Ni(IV) intermediate.[11]

The Kumada coupling has been successfully demonstrated for a variety of aryl or vinyl halides. In place of the halide reagent pseudohalides can also be used, and the coupling has been shown to be quite effective using tosylate[12] and triflate[13] species in variety of conditions.

Despite broad success with aryl and vinyl couplings, the use of alkyl halides is less general due to several complicating factors. Having no π-electrons, alkyl halides require different oxidative addition mechanisms than aryl or vinyl groups, and these processes are currently poorly understood.[9] Additionally, the presence of β-hydrogens makes alkyl halides susceptible to competitive elimination processes.[14]

These issues have been circumvented by the presence of an activating group, such as the carbonyl in α-bromoketones, that drives the reaction forward. However, Kumada couplings have also been performed with non-activated alkyl chains, often through the use of additional catalysts or reagents. For instance, with the addition of 1,3-butadienes Kambe and coworkers demonstrated nickel catalyzed alkyl–alkyl couplings that would otherwise be unreactive.[15]

Though poorly understood, the mechanism of this reaction is proposed to involve the formation of an octadienyl nickel complex. This catalyst is proposed to undergo transmetalation with a Grignard reagent first, prior to the reductive elimination of the halide, reducing the risk of β-hydride elimination. However, the presence of a Ni(IV) intermediate is contrary to mechanisms proposed for aryl or vinyl halide couplings.[11]

Couplings involving aryl and vinyl Grignard reagents were reported in the original publications by Kumada and Corriu.[2] Alkyl Grignard reagents can also be used without difficulty, as they do not suffer from β-hydride elimination processes. Although the Grignard reagent inherently has poor functional group tolerance, low-temperature syntheses have been prepared with highly functionalized aryl groups.[16]

Kumada couplings can be performed with a variety of nickel(II) or palladium(II) catalysts. The structures of the catalytic precursors can be generally formulated as ML2X2, where L is a phosphine ligand.[17] Common choices for L2 include bidentate diphosphine ligands such as dppe and dppp among others.

Work by Alois Fürstner and coworkers on iron-based catalysts have shown reasonable yields. The catalytic species in these reactions is proposed to be an "inorganic Grignard reagent" consisting of Fe(MgX)2.[18]

The reaction typically is carried out in tetrahydrofuran or diethyl ether as solvent. Such ethereal solvents are convenient because these are typical solvents for generating the Grignard reagent.[2] Due to the high reactivity of the Grignard reagent, Kumada couplings have limited functional group tolerance which can be problematic in large syntheses. In particular, Grignard reagents are sensitive to protonolysis from even mildly acidic groups such as alcohols. They also add to carbonyls and other oxidative groups.

As in many coupling reactions, the transition metal palladium catalyst is often air-sensitive, requiring an inert Argon or nitrogen reaction environment.

A sample synthetic preparation is available at the Organic Syntheses website.

Both cis- and trans-olefin halides promote the overall retention of geometric configuration when coupled with alkyl Grignards. This observation is independent of other factors, including the choice of catalyst ligands and vinylic substituents.[17]

Conversely, a Kumada coupling using vinylic Grignard reagents proceeds without stereospecificity to form a mixture of cis- and trans-alkenes. The degree of isomerization is dependent on a variety of factors including reagent ratios and the identity of the halide group. According to Kumada, this loss of stereochemistry is attributable to side-reactions between two equivalents of the allylic Grignard reagent.[17]

Asymmetric Kumada couplings can be effected through the use of chiral ligands. Using planar chiral ferrocene ligands, enantiomeric excesses (ee) upward of 95% have been observed in aryl couplings.[19] More recently, Gregory Fu and co-workers have demonstrated enantioconvergent couplings of α-bromoketones using catalysts based on bis-oxazoline ligands, wherein the chiral catalyst converts a racemic mixture of starting material to one enantiomer of product with up to 95% ee.[20] The latter reaction is also significant for involving a traditionally inaccessible alkyl halide coupling.

Grignard reagents do not typically couple with chlorinated arenes. This low reactivity is the basis for chemoselectivity for nickel insertion into the C–Br bond of bromochlorobenzene using a NiCl2-based catalyst.[21]

The Kumada coupling is suitable for large-scale, industrial processes, such as drug synthesis. The reaction is used to construct the carbon skeleton of aliskiren (trade name Tekturna), a treatment for hypertension.[22]

The Kumada coupling also shows promise in the synthesis of conjugated polymers, polymers such as polyalkylthiophenes (PAT), which have a variety of potential applications in organic solar cells and light-emitting diodes.[23] In 1992, McCollough and Lowe developed the first synthesis of regioregular polyalkylthiophenes by utilizing the Kumada coupling scheme pictured below, which requires subzero temperatures.[24]

Since this initial preparation, the synthesis has been improved to obtain higher yields and operate at room temperature.[25]

Heck reaction

Hiyama coupling

Suzuki reaction

Negishi coupling

Petasis reaction

Stille reaction

Sonogashira coupling

1. Corriu, R. J. P.; Masse, J. P. (1 January 1972). "Activation of Grignard reagents by transition-metal complexes. A new and simple synthesis of trans-stilbenes and polyphenyls". Journal of the Chemical Society, Chemical Communications (3): 144a. doi:10.1039/C3972000144A.
2. Tamao, Kohei; Sumitani, Koji; Kumada, Makoto (1 June 1972). "Selective carbon–carbon bond formation by cross-coupling of Grignard reagents with organic halides. Catalysis by nickel-phosphine complexes". Journal of the American Chemical Society. 94 (12): 4374–4376. doi:10.1021/ja00767a075.
3. Kharasch, M. S.; Fields, E. K. (1 September 1941). "Factors Determining the Course and Mechanisms of Grignard Reactions. IV. The Effect of Metallic Halides on the Reaction of Aryl Grignard Reagents and Organic Halides1". Journal of the American Chemical Society. 63 (9): 2316–2320. doi:10.1021/ja01854a006.
4. Jay K. Kochi and Masuhiko Tamura (1971). "Mechanism of the silver-catalyzed reaction of Grignard reagents with alkyl halides". J. Am. Chem. Soc. 93 (6): 1483–1485. doi:10.1021/ja00735a028.
5. Kochi, Jay K.; Tamura, Masuhiko (1 March 1971). "Alkylcopper(I) in the coupling of Grignard reagents with alkyl halides". Journal of the American Chemical Society. 93 (6): 1485–1487. doi:10.1021/ja00735a029.
6. Tamura, Masuhiko; Kochi, Jay K. (1 March 1971). "Vinylation of Grignard reagents. Catalysis by iron". Journal of the American Chemical Society. 93 (6): 1487–1489. doi:10.1021/ja00735a030.
7. Yamamura, Masaaki; Moritani, Ichiro; Murahashi, Shun-Ichi (27 May 1975). "The reaction of σ-vinylpalladium complexes with alkyllithiums. Stereospecific syntheses of olefins from vinyl halides and alkyllithiums". Journal of Organometallic Chemistry. 91 (2): C39–C42. doi:10.1016/S0022-328X(00)89636-9.
8. Knappke, Christiane E. I.; Jacobi von Wangelin, Axel (2011). "35 years of palladium-catalyzed cross-coupling with Grignard reagents: how far have we come?". Chemical Society Reviews. 40 (10): 4948–62. doi:10.1039/c1cs15137a. PMID 21811712.
9. Hu, Xile (2011). "Nickel-catalyzed cross coupling of non-activated alkyl halides: a mechanistic perspective". Chem. Sci. 2 (10): 1867–1886. doi:10.1039/c1sc00368b.
10. Jones, Gavin D.; McFarland, Chris; Anderson, Thomas J.; Vicic, David A. (1 January 2005). "Analysis of key steps in the catalytic cross-coupling of alkyl electrophiles under Negishi-like conditions". Chemical Communications (33): 4211–3. doi:10.1039/b504996b. PMID 16100606.
11. Frisch, Anja C.; Beller, Matthias (21 January 2005). "Catalysts for Cross-Coupling Reactions with Non-activated Alkyl Halides". Angewandte Chemie International Edition. 44 (5): 674–688. doi:10.1002/anie.200461432. PMID 15657966.
12. Limmert, Michael E.; Roy, Amy H.; Hartwig, John F. (1 November 2005). "Kumada Coupling of Aryl and Vinyl Tosylates under Mild Conditions". The Journal of Organic Chemistry. 70 (23): 9364–9370. doi:10.1021/jo051394l. PMID 16268609.
13. Busacca, Carl A.; Eriksson, Magnus C.; Fiaschi, Rita (1999). "Cross coupling of vinyl triflates and alkyl Grignard reagents catalyzed by nickel(0)-complexes". Tetrahedron Letters. 40 (16): 3101–3104. doi:10.1016/S0040-4039(99)00439-6.
14. Rudolph, Alena; Lautens, Mark (30 March 2009). "Secondary Alkyl Halides in Transition-Metal-Catalyzed Cross-Coupling Reactions". Angewandte Chemie International Edition. 48 (15): 2656–2670. doi:10.1002/anie.200803611. PMID 19173365.
15. Terao, Jun; Watanabe, Hideyuki; Ikumi, Aki; Kuniyasu, Hitoshi; Kambe, Nobuaki (1 April 2002). "Nickel-Catalyzed Cross-Coupling Reaction of Grignard Reagents with Alkyl Halides and Tosylates: Remarkable Effect of 1,3-Butadienes". Journal of the American Chemical Society. 124 (16): 4222–4223. doi:10.1021/ja025828v. PMID 11960446.
16. Adrio, Javier; Carretero, Juan C. (15 November 2010). "Functionalized Grignard Reagents in Kumada Cross-Coupling Reactions". ChemCatChem. 2 (11): 1384–1386. doi:10.1002/cctc.201000237. S2CID 98429919.
17. Kumada, M. (1 January 1980). "Nickel and palladium complex catalyzed cross-coupling reactions of organometallic reagents with organic halides". Pure and Applied Chemistry. 52 (3): 669–679. doi:10.1351/pac198052030669.
18. Fürstner, Alois; Leitner, Andreas; Méndez, María; Krause, Helga (1 November 2002). "Iron-Catalyzed Cross-Coupling Reactions". Journal of the American Chemical Society. 124 (46): 13856–13863. doi:10.1021/ja027190t. PMID 12431116.
19. Hayashi, Tamio; Yamamoto, Akihiro; Hojo, Masahiro; Kishi, Kohei; Ito, Yoshihiko; Nishioka, Eriko; Miura, Hitoshi; Yanagi, Kazunori (1989). "Asymmetric synthesis catalyzed by chiral ferrocenylphosphine-transition metal complexes". Journal of Organometallic Chemistry. 370 (1–3): 129–139. doi:10.1016/0022-328X(89)87280-8.
20. Lou, Sha; Fu, Gregory C. (3 February 2010). "Nickel/Bis(oxazoline)-Catalyzed Asymmetric Kumada Reactions of Alkyl Electrophiles: Cross-Couplings of Racemic α-Bromoketones". Journal of the American Chemical Society. 132 (4): 1264–1266. doi:10.1021/ja909689t. PMC 2814537. PMID 20050651.
21. Ikoma, Yoshiharu; Ando, Kazuhiko; Naoi, Yoshitake; Akiyama, Takeo; Sugimori, Akira (1 February 1991). "Halogen Selectivity in Nickel Salt-Catalyzed Cross-Coupling of Aryl Grignard Reagents with Bromochlorobenzenes a Novel Synthetic Method of Unsymmetrical Terphenyl". Synthetic Communications. 21 (3): 481–487. doi:10.1080/00397919108016772.
22. Johnson and Lee (2010). Modern Drug Synthesis. Hoboken, NJ: John Wiley & Sons, Inc. pp. 153–154. ISBN 978-0-470-52583-8.
23. Cheng, Yen-Ju; Yang, Sheng-Hsiung; Hsu, Chain-Shu (11 November 2009). "Synthesis of Conjugated Polymers for Organic Solar Cell Applications". Chemical Reviews. 109 (11): 5868–5923. doi:10.1021/cr900182s. PMID 19785455.
24. McCullough, Richard D.; Lowe, Renae D. (1 January 1992). "Enhanced electrical conductivity in regioselectively synthesized poly(3-alkylthiophenes)". Journal of the Chemical Society, Chemical Communications (1): 70. doi:10.1039/C39920000070.
25. Loewe, Robert S.; Ewbank, Paul C.; Liu, Jinsong; Zhai, Lei; McCullough, Richard D. (1 June 2001). "Regioregular, Head-to-Tail Coupled Poly(3-alkylthiophenes) Made Easy by the GRIM Method: Investigation of the Reaction and the Origin of Regioselectivity". Macromolecules. 34 (13): 4324–4333. doi:10.1021/ma001677+.

The reaction couples organic halides or triflates with organozinc compounds, forming carbon-carbon bonds (C-C) in the process. A palladium (0) species is generally utilized as the metal catalyst, though nickel is sometimes used.[1][2] A variety of nickel catalysts in either Ni0 or NiII oxidation state can be employed in Negishi cross couplings such as Ni(PPh3)4, Ni(acac)2, Ni(COD)2 etc.[3][4][5]

• The leaving group X is usually chloride, bromide, or iodide, but triflate and acetyloxy groups are feasible as well. X = Cl usually leads to slow reactions.
• The organic residue R = alkenyl, aryl, allyl, alkynyl or propargyl.
• The halide X' in the organozinc compound can be chloride, bromine or iodine and the organic residue R' is alkenyl, aryl, allyl, alkyl, benzyl, homoallyl, and homopropargyl.
• The metal M in the catalyst is nickel or palladium
• The ligand L in the catalyst can be triphenylphosphine, dppe, BINAP or chiraphos

Palladium catalysts in general have higher chemical yields and higher functional group tolerance.

The Negishi coupling finds common use in the field of total synthesis as a method for selectively forming C-C bonds between complex synthetic intermediates. The reaction allows for the coupling of sp3, sp2, and sp carbon atoms, (see orbital hybridization) which make it somewhat unusual among the palladium-catalyzed coupling reactions. Organozincs are moisture and air sensitive, so the Negishi coupling must be performed in an oxygen and water free environment, a fact that has hindered its use relative to other cross-coupling reactions that require less robust conditions (i.e. Suzuki reaction). However, organozincs are more reactive than both organostannanes and organoborates which correlates to faster reaction times.

The reaction is named after Ei-ichi Negishi who was a co-recipient of the 2010 Nobel Prize in Chemistry for the discovery and development of this reaction.

Negishi and coworkers originally investigated the cross-coupling of organoaluminum reagents in 1976 initially employing Ni and Pd as the transition metal catalysts, but noted that Ni resulted in the decay of stereospecifity whereas Pd did not.[6] Transitioning from organoaluminum species to organozinc compounds Negishi and coworkers reported the use of Pd complexes in organozinc coupling reactions and carried out methods studies, eventually developing the reaction conditions into those commonly utilized today.[7] Alongside Richard F. Heck and Akira Suzuki, El-ichi Negishi was a co-recipient of the Nobel Prize in Chemistry in 2010, for his work on "palladium-catalyzed cross couplings in organic synthesis".

The reaction mechanism is thought to proceed via a standard Pd catalyzed cross-coupling pathway, starting with a Pd(0) species, which is oxidized to Pd(II) in an oxidative addition step involving the organohalide species.[8] This step proceeds with aryl, vinyl, alkynyl, and acyl halides, acetates, or triflates, with substrates following standard oxidative addition relative rates (I>OTf>Br>>Cl).[9]

The actual mechanism of oxidative addition is unresolved, though there are two likely pathways. One pathway is thought to proceed via an SN2 like mechanism resulting in inverted stereochemistry. The other pathway proceeds via concerted addition and retains stereochemistry.

Though the additions are cis- the Pd(II) complex rapidly isomerizes to the trans- complex.[10]

Next, the transmetalation step occurs where the organozinc reagent exchanges its organic substituent with the halide in the Pd(II) complex, generating the trans- Pd(II) complex and a zinc halide salt. The organozinc substrate can be aryl, vinyl, allyl, benzyl, homoallyl, or homopropargyl.[8] Transmetalation is usually rate limiting and a complete mechanistic understanding of this step has not yet been reached though several studies have shed light on this process. It was recently determined that alkylzinc species must go on to form a higher-order zincate species prior to transmetalation whereas arylzinc species do not.[11] ZnXR and ZnR2 can both be used as reactive reagents, and Zn is known to prefer four coordinate complexes, which means solvent coordinated Zn complexes, such as ZnXR(solvent)2 cannot be ruled out a priori.[12] Studies indicate competing equilibriums exist between cis- and trans- bis alkyl organopalladium complexes, but that the only productive intermediate is the cis complex.[13][14]

The last step in the catalytic pathway of the Negishi coupling is reductive elimination, which is thought to proceed via a three coordinate transition state, yielding the coupled organic product and regenerating the Pd(0) catalyst. For this step to occur, the aforementioned cis- alkyl organopalladium complex must be formed.[15]

Both organozinc halides and diorganozinc compounds can be used as starting materials. In one model system it was found that in the transmetalation step the former give the cis-adduct R-Pd-R' resulting in fast reductive elimination to product while the latter gives the trans-adduct which has to go through a slow trans-cis isomerization first.[13]

A common side reaction is homocoupling. In one Negishi model system the formation of homocoupling was found to be the result of a second transmetalation reaction between the diarylmetal intermediate and arylmetal halide:[16]

Ar–Pd–Ar' + Ar'–Zn–X → Ar'–Pd–Ar' + Ar–Zn–X

Ar'–Pd–Ar' → Ar'–Ar' + Pd(0) (homocoupling)

Ar–Zn–X + H2O → Ar–H + HO–Zn–X (reaction accompanied by dehalogenation)

Nickel catalyzed systems can operate under different mechanisms depending on the coupling partners. Unlike palladium systems which involve only Pd0 or PdII, nickel catalyzed systems can involve nickel of different oxidation states.[17] Both systems are similar in that they involve similar elementary steps: oxidative addition, transmetalation, and reductive elimination. Both systems also have to address issues of β-hydride elimination and difficult oxidative addition of alkyl electrophiles.[18]

For unactivated alkyl electrophiles, one possible mechanism is a transmetalation first mechanism. In this mechanism, the alkyl zinc species would first transmetalate with the nickel catalyst. Then the nickel would abstract the halide from the alkyl halide resulting in the alkyl radical and oxidation of nickel after addition of the radical.[19]

One important factor when contemplating the mechanism of a nickel catalyzed cross coupling is that reductive elimination is facile from NiIII species, but very difficult from NiII species. Kochi and Morrell provided evidence for this by isolating NiII complex Ni(PEt3)2(Me)(o-tolyl), which did not undergo reductive elimination quickly enough to be involved in this elementary step.[20]

The Negishi coupling has been applied the following illustrative syntheses:

• unsymmetrical 2,2'-bipyridines from 2-bromopyridine with tetrakis(triphenylphosphine)palladium(0),[21]
• biphenyl from o-tolylzinc chloride and o-iodotoluene and tetrakis(triphenylphosphine)palladium(0),[22]
• 5,7-hexadecadiene from 1-decyne and (Z)-1-hexenyl iodide.[23]

Negishi coupling has been applied in the synthesis of hexaferrocenylbenzene:[24]

with hexaiodidobenzene, diferrocenylzinc and tris(dibenzylideneacetone)dipalladium(0) in tetrahydrofuran. The yield is only 4% signifying substantial crowding around the aryl core.

In a novel modification palladium is first oxidized by the haloketone 2-chloro-2-phenylacetophenone 1 and the resulting palladium OPdCl complex then accepts both the organozinc compound 2 and the organotin compound 3 in a double transmetalation:[25]

Recent conditions for the Negishi reaction have demonstrated extremely broad scope and tolerance of a broad range of functional groups and heteroaromatic nuclei and proceed at or near room temperature.[26]

Examples of nickel catalyzed Negishi couplings include sp2-sp2, sp2-sp3, and sp3-sp3 systems. In the system first studied by Negishi, aryl-aryl cross coupling was catalyzed by Ni(PPh3)4 generated in situ through reduction of Ni(acac)2 with PPh3 and (i-Bu)2AlH.[27]

Variations have also been developed to allow for the cross-coupling of aryl and alkenyl partners. In the variation developed by Knochel et al, aryl zinc bromides were reacted with vinyl triflates and vinyl halides.[28]

Reactions between sp3-sp3 centers are often more difficult; however, adding an unsaturated ligand with an electron withdrawing group as a cocatalyst improved the yield in some systems. It is believed that added coordination from the unsaturated ligand favors reductive elimination over β-hydride elimination.[29][30] This also works in some alkyl-aryl systems.[31]

Several asymmetric variants exist and many utilize Pybox ligands.[32][33][34]

The Negishi coupling is not employed as frequently in industrial applications as its cousins the Suzuki reaction and Heck reaction, mostly as a result of the water and air sensitivity of the required aryl or alkyl zinc reagents.[35][36] In 2003 Novartis employed a Negishi coupling in the manufacture of PDE472, a phosphodiesterase type 4D inhibitor, which was being investigated as a drug lead for the treatment of asthma.[37] The Negishi coupling was used as an alternative to the Suzuki reaction providing improved yields, 73% on a 4.5 kg scale, of the desired benzodioxazole synthetic intermediate.[38]

Where the Negishi coupling is rarely used in industrial chemistry, a result of the aforementioned water and oxygen sensitivity, it finds wide use in the field of natural products total synthesis. The increased reactivity relative to other cross-coupling reactions makes the Negishi coupling ideal for joining complex intermediates in the synthesis of natural products.[8] Additionally, Zn is more environmentally friendly than other metals such as Sn used in the Stille coupling. Though the Negishi coupling historically has not been used as much as the Stille or Suzuki coupling, recent years have seen the Negishi coupling gain a foothold in the field of synthetic chemistry, so much so that it has become the cross-coupling method of choice for select synthetic tasks. When it comes to fragment-coupling processes the Negishi coupling is particularly useful, especially when compared to the aforementioned Stille and Suzuki coupling reactions.[39] The major drawback of the Negishi coupling, aside from its water and oxygen sensitivity, is its relative lack of functional group tolerance when compared to other cross-coupling reactions.[40]

(−)-stemoamide is a natural product found in the root extracts of ‘’Stemona tuberosa’’. These extracts have been used Japanese and Chinese folk medicine to treat respiratory disorders, and (−)-stemoamide is also an anthelminthic. Somfai and coworkers employed a Negishi coupling in their synthesis of (−)-stemoamide.[41] The reaction was implemented mid-synthesis, forming an sp3-sp2 c-c bond between β,γ-unsaturated ester and an intermediate diene 4 with a 78% yield of product 5. Somfai completed the stereoselective total synthesis of (−)-stemoamide in 12-steps with a 20% overall yield.

Kibayashi and coworkers utilized the Negishi coupling in the total synthesis of Pumiliotoxin B. Pumiliotoxin B is one of the major toxic alkaloids isolated from Dendrobates pumilio, a Panamanian poison frog. These toxic alkaloids display modulatory effects on voltage-dependent sodium channels, resulting in cardiotonic and myotonic activity.[42] Kibayashi employed the Negishi coupling late stage in the synthesis of Pumiliotoxin B, coupling a homoallylic sp3 carbon on the zinc alkylidene indolizidine 6 with the (E)-vinyl iodide 7 with a 51% yield. The natural product was then obtained after deprotection.[43]

δ-trans-tocotrienoloic acid isolated from the plant, Chrysochlamys ulei, is a natural product shown to inhibit DNA polymerase β (pol β), which functions to repair DNA via base excision. Inhibition of pol B in conjunction with other chemotherapy drugs may increase the cytotoxicity of these chemotherapeutics, leading to lower effective dosages. The Negishi coupling was implemented in the synthesis of δ-trans-tocotrienoloic acid by Hecht and Maloney coupling the sp3 homopropargyl zinc reagent 8 with sp2 vinyl iodide 9.[44] The reaction proceeded with quantitative yield, coupling fragments mid-synthesis en route to the stereoselectively synthesized natural product δ-trans-tocotrienoloic acid.

Smith and Fu demonstrated that their method to couple secondary nucleophiles with secondary alkyl electrophiles could be applied to the formal synthesis of α-cembra-2,7,11-triene-4,6-diol, a target with antitumor activity. They achieved a 61% yield on a gram scale using their method to install an iso-propyl group. This method would be highly adaptable in this application for diversification and installing other alkyl groups to enable structure-activbity relationship (SAR) studies.[45]

Kirschning and Schmidt applied nickel catalyzed negishi cross-coupling to the first total synthesis of carolactone. In this application, they achieved 82% yield and dr = 10:1.[46]

Alkylzinc reagents can be accessed from the corresponding alkyl bromides using iodine in dimethylacetamide (DMAC).[47] The catalytic I2 serves to activate the zinc towards nucleophilic addition.

Aryl zincs can be synthesized using mild reaction conditions via a Grignard like intermediate.[48]

Organozincs can also be generated in situ and used in a one pot procedure as demonstrated by Knochel et. al.[49]

CPhos

Heck reaction

Suzuki reaction

1. King AO, Okukado N, Negishi E (1977). "Highly general stereo-, regio-, and chemo-selective synthesis of terminal and internal conjugated enynes by the Pd-catalysed reaction of alkynylzinc reagents with alkenyl halides". Journal of the Chemical Society, Chemical Communications (19): 683. doi:10.1039/C39770000683.
2. Kürti L, Czakó B (2007). Strategic applications of named reactions in organic synthesis : background and detailed mechanisms ; 250 named reactions. Amsterdam: Elsevier Academic Press. ISBN 978-0-12-429785-2.
3. Zhou, Jianrong (Steve); Fu, Gregory C. (December 2003). "Cross-Couplings of Unactivated Secondary Alkyl Halides: Room-Temperature Nickel-Catalyzed Negishi Reactions of Alkyl Bromides and Iodides". Journal of the American Chemical Society. 125 (48): 14726–14727. doi:10.1021/ja0389366. ISSN 0002-7863. PMID 14640646.
4. Negishi, Eiichi; King, Anthony O.; Okukado, Nobuhisa (1977-05-01). "Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides". The Journal of Organic Chemistry. 42 (10): 1821–1823. doi:10.1021/jo00430a041. ISSN 0022-3263.
5. Gavryushin, Andrei; Kofink, Christiane; Manolikakes, Georg; Knochel, Paul (2005-10-01). "Efficient Cross-Coupling of Functionalized Arylzinc Halides Catalyzed by a Nickel Chloride−Diethyl Phosphite System". Organic Letters. 7 (22): 4871–4874. doi:10.1021/ol051615+. ISSN 1523-7060. PMID 16235910.
6. Baba S, Negishi E (1976). "A novel stereospecific alkenyl-alkenyl cross-coupling by a palladium- or nickel-catalyzed reaction of alkenylalanes with alkenyl halides". Journal of the American Chemical Society. 98 (21): 6729–6731. doi:10.1021/ja00437a067.
7. Negishi E, King AO, Okukado N (1977). "Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides". The Journal of Organic Chemistry. 42 (10): 1821–1823. doi:10.1021/jo00430a041.
8. Kurti L, Czako B (2005). Strategic Applications of Named Reactions in Organic Synthesis. New York: Elsevier Academic Press.
9. Andrew G Myers Research Group. "Chemistry 115 Handouts". Boston, Massachusetts: Harvard University Department of Chemistry.
10. Casado AL, Espinet P (1998). "On the Configuration Resulting from Oxidative Addition of RX to Pd(PPh3)4 and the Mechanism of the cis-to-trans Isomerization of [PdRX(PPh3)2] Complexes (R = Aryl, X = Halide)". Organometallics. 17 (5): 954–959. doi:10.1021/om9709502.
11. McCann LC, Hunter HN, Clyburne JA, Organ MG (July 2012). "Higher-order zincates as transmetalators in alkyl-alkyl negishi cross-coupling". Angewandte Chemie. 51 (28): 7024–7. doi:10.1002/anie.201203547. PMID 22685029.
12. García-Melchor M, Braga AA, Lledós A, Ujaque G, Maseras F (November 2013). "Computational perspective on Pd-catalyzed C-C cross-coupling reaction mechanisms". Accounts of Chemical Research. 46 (11): 2626–34. doi:10.1021/ar400080r. PMID 23848308.
13. Casares JA, Espinet P, Fuentes B, Salas G (March 2007). "Insights into the mechanism of the Negishi reaction: ZnRX versus ZnR2 reagents". Journal of the American Chemical Society. 129 (12): 3508–9. doi:10.1021/ja070235b. PMID 17328551.
14. Fuentes B, García-Melchor M, Lledós A, Maseras F, Casares JA, Ujaque G, Espinet P (August 2010). "Palladium round trip in the Negishi coupling of trans-[PdMeCl(PMePh2)2] with ZnMeCl: an experimental and DFT study of the transmetalation step". Chemistry. 16 (29): 8596–9. doi:10.1002/chem.201001332. PMID 20623568.
15. Crabtree R (2005). The Organometallic Chemistry of the Transition Metals. Vol. 4. Hoboken, NJ: John Wiley and Sons Inc.
16. Liu Q, Lan Y, Liu J, Li G, Wu YD, Lei A (July 2009). "Revealing a second transmetalation step in the Negishi coupling and its competition with reductive elimination: improvement in the interpretation of the mechanism of biaryl syntheses". Journal of the American Chemical Society. 131 (29): 10201–10. doi:10.1021/ja903277d. PMID 19572717.
17. Phapale, Vilas B.; Cárdenas, Diego J. (2009-05-27). "Nickel-catalysed Negishi cross-coupling reactions: scope and mechanisms". Chemical Society Reviews. 38 (6): 1598–1607. doi:10.1039/B805648J. ISSN 1460-4744. PMID 19587955.
18. Zhou, Jianrong (Steve); Fu, Gregory C. (December 2003). "Cross-Couplings of Unactivated Secondary Alkyl Halides: Room-Temperature Nickel-Catalyzed Negishi Reactions of Alkyl Bromides and Iodides". Journal of the American Chemical Society. 125 (48): 14726–14727. doi:10.1021/ja0389366. ISSN 0002-7863. PMID 14640646.
19. Schley, Nathan D.; Fu, Gregory C. (2014-11-26). "Nickel-Catalyzed Negishi Arylations of Propargylic Bromides: A Mechanistic Investigation". Journal of the American Chemical Society. 136 (47): 16588–16593. doi:10.1021/ja508718m. ISSN 0002-7863. PMC 4277758. PMID 25402209.
20. Morrell, Dennis G.; Kochi, Jay K. (1975-12-01). "Mechanistic studies of nickel catalysis in the cross coupling of aryl halides with alkylmetals. Role of arylalkylnickel(II) species as intermediates". Journal of the American Chemical Society. 97 (25): 7262–7270. doi:10.1021/ja00858a011. ISSN 0002-7863.
21. Adam P. Smith, Scott A. Savage, J. Christopher Love, and Cassandra L. Fraser (2004). "Synthesis of 4-, 5-, and 6-methyl-2,2'-bipyridine by a Negishi cross-coupling strategy: 5-methyl-2,2'-bipyridine". Organic Syntheses.; Collective Volume, vol. 10, p. 517
22. Ei-ichi Negishi, Tamotsu Takahashi, and Anthony O. King (1993). "Synthesis of biaryls via palladium-catalyzed cross-coupling: 2-methyl-4'-nitrobiphenyl". Organic Syntheses.; Collective Volume, vol. 8, p. 430
23. Ei-ichi Negishi, Tamotsu Takahashi, and Shigeru Baba (1993). "Palladium-catalyzed synthesis of conjugated dienes". Organic Syntheses.; Collective Volume, vol. 8, p. 295
24. Yu Y, Bond AD, Leonard PW, Lorenz UJ, Timofeeva TV, Vollhardt KP, Whitener GD, Yakovenko AA (June 2006). "Hexaferrocenylbenzene". Chemical Communications (24): 2572–4. doi:10.1039/b604844g. PMID 16779481.
25. Zhao Y, Wang H, Hou X, Hu Y, Lei A, Zhang H, Zhu L (November 2006). "Oxidative cross-coupling through double transmetallation: surprisingly high selectivity for palladium-catalyzed cross-coupling of alkylzinc and alkynylstannanes". Journal of the American Chemical Society. 128 (47): 15048–9. doi:10.1021/ja0647351. PMID 17117830.
26. Yang Y, Oldenhuis NJ, Buchwald SL (January 2013). "Mild and general conditions for negishi cross-coupling enabled by the use of palladacycle precatalysts". Angewandte Chemie. 52 (2): 615–9. doi:10.1002/anie.201207750. PMC 3697109. PMID 23172689.
27. Negishi, Eiichi; King, Anthony O.; Okukado, Nobuhisa (1977-05-01). "Selective carbon-carbon bond formation via transition metal catalysis. 3. A highly selective synthesis of unsymmetrical biaryls and diarylmethanes by the nickel- or palladium-catalyzed reaction of aryl- and benzylzinc derivatives with aryl halides". The Journal of Organic Chemistry. 42 (10): 1821–1823. doi:10.1021/jo00430a041. ISSN 0022-3263.
28. Gavryushin, Andrei; Kofink, Christiane; Manolikakes, Georg; Knochel, Paul (2005-10-01). "Efficient Cross-Coupling of Functionalized Arylzinc Halides Catalyzed by a Nickel Chloride−Diethyl Phosphite System". Organic Letters. 7 (22): 4871–4874. doi:10.1021/ol051615+. ISSN 1523-7060. PMID 16235910.
29. Giovannini, Riccardo; Stüdemann, Thomas; Dussin, Gaelle; Knochel, Paul (1998). "An Efficient Nickel-Catalyzed Cross-Coupling Between sp3 Carbon Centers". Angewandte Chemie International Edition. 37 (17): 2387–2390. doi:10.1002/(SICI)1521-3773(19980918)37:17<2387::AID-ANIE2387>3.0.CO;2-M. ISSN 1521-3773. PMID 29710957.
30. Jensen, Anne Eeg; Knochel, Paul (2002-01-01). "Nickel-Catalyzed Cross-Coupling between Functionalized Primary or Secondary Alkylzinc Halides and Primary Alkyl Halides". The Journal of Organic Chemistry. 67 (1): 79–85. doi:10.1021/jo0105787. ISSN 0022-3263. PMID 11777442.
31. Giovannini, Riccardo; Knochel, Paul (1998-11-01). "Ni(II)-Catalyzed Cross-Coupling between Polyfunctional Arylzinc Derivatives and Primary Alkyl Iodides". Journal of the American Chemical Society. 120 (43): 11186–11187. doi:10.1021/ja982520o. ISSN 0002-7863.
32. Fischer, Christian; Fu, Gregory C. (April 2005). "Asymmetric Nickel-Catalyzed Negishi Cross-Couplings of Secondary α-Bromo Amides with Organozinc Reagents". Journal of the American Chemical Society. 127 (13): 4594–4595. doi:10.1021/ja0506509. ISSN 0002-7863. PMID 15796523.
33. Son, Sunghee; Fu, Gregory C. (2008-03-01). "Nickel-Catalyzed Asymmetric Negishi Cross-Couplings of Secondary Allylic Chlorides with Alkylzincs". Journal of the American Chemical Society. 130 (9): 2756–2757. doi:10.1021/ja800103z. ISSN 0002-7863. PMID 18257579.
34. Phapale, Vilas B.; Buñuel, Elena; García-Iglesias, Miguel; Cárdenas, Diego J. (2007). "Ni-Catalyzed Cascade Formation of C(sp3)C(sp3) Bonds by Cyclization and Cross-Coupling Reactions of Iodoalkanes with Alkyl Zinc Halides". Angewandte Chemie International Edition. 46 (46): 8790–8795. doi:10.1002/anie.200702528. ISSN 1521-3773. PMID 17918274.
35. Johansson Seechurn CC, Kitching MO, Colacot TJ, Snieckus V (May 2012). "Palladium-catalyzed cross-coupling: a historical contextual perspective to the 2010 Nobel Prize". Angewandte Chemie. 51 (21): 5062–85. doi:10.1002/anie.201107017. PMID 22573393.
36. Sase S, Jaric M, Metzger A, Malakhov V, Knochel P (September 2008). "One-pot Negishi cross-coupling reactions of in situ generated zinc reagents with aryl chlorides, bromides, and triflates". The Journal of Organic Chemistry. 73 (18): 7380–2. doi:10.1021/jo801063c. PMID 18693766.
37. Manley PW, Acemoglu M, Marterer W, Pachinger W (2003). "Large-Scale Negishi Coupling as Applied to the Synthesis of PDE472, an Inhibitor of Phosphodiesterase Type 4D". Organic Process Research & Development. 7 (3): 436–445. doi:10.1021/op025615q.
38. Torborg C, Beller M (2009). "Recent Applications of Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries". Advanced Synthesis & Catalysis. 351 (18): 3027–3043. doi:10.1002/adsc.200900587.
39. Nicolaou KC, Bulger PG, Sarlah D (July 2005). "Palladium-catalyzed cross-coupling reactions in total synthesis". Angewandte Chemie. 44 (29): 4442–89. doi:10.1002/anie.200500368. PMID 15991198.
40. Lessene G (2004). "Advances in the Negishi coupling". Aust. J. Chem. 57 (1): 107. doi:10.1071/ch03225.
41. Torssell S, Wanngren E, Somfai P (May 2007). "Total synthesis of (-)-stemoamide". The Journal of Organic Chemistry. 72 (11): 4246–9. doi:10.1021/jo070498o. PMID 17451274.
42. Gusovsky F, Padgett WL, Creveling CR, Daly JW (December 1992). "Interaction of pumiliotoxin B with an "alkaloid-binding domain" on the voltage-dependent sodium channel". Molecular Pharmacology. 42 (6): 1104–8. PMID 1336116.
43. Aoyagi S, Hirashima S, Saito K, Kibayashi C (2002). "Convergent Approach to Pumiliotoxin Alkaloids. Asymmetric Total Synthesis of (+)-Pumiliotoxins A, B, and 225F". The Journal of Organic Chemistry. 67 (16): 5517–5526. doi:10.1021/jo0200466. PMID 12153249.
44. Maloney DJ, Hecht SM (September 2005). "A stereocontrolled synthesis of delta-trans-tocotrienoloic acid". Organic Letters. 7 (19): 4297–300. doi:10.1021/ol051849t. PMID 16146411.
45. Smith, Sean W.; Fu, Gregory C. (2008). "Nickel-Catalyzed Negishi Cross-Couplings of Secondary Nucleophiles with Secondary Propargylic Electrophiles at Room Temperature". Angewandte Chemie International Edition. 47 (48): 9334–9336. doi:10.1002/anie.200802784. ISSN 1521-3773. PMC 2790060. PMID 18972493.
46. Schmidt, Thomas; Kirschning, Andreas (2012). "Total Synthesis of Carolacton, a Highly Potent Biofilm Inhibitor". Angewandte Chemie International Edition. 51 (4): 1063–1066. doi:10.1002/anie.201106762. ISSN 1521-3773. PMID 22162345.
47. Huo S (February 2003). "Highly efficient, general procedure for the preparation of alkylzinc reagents from unactivated alkyl bromides and chlorides". Organic Letters. 5 (4): 423–5. doi:10.1021/ol0272693. PMID 12583734.
48. Giovannini R, Knochel P (1998). "Ni(II)-Catalyzed Cross-Coupling between Polyfunctional Arylzinc Derivatives and Primary Alkyl Iodides". Journal of the American Chemical Society. 120 (43): 11186–11187. doi:10.1021/ja982520o.
49. Sase, Shohei; Jaric, Milica; Metzger, Albrecht; Malakhov, Vladimir; Knochel, Paul (2008-09-19). "One-Pot Negishi Cross-Coupling Reactions of In Situ Generated Zinc Reagents with Aryl Chlorides, Bromides, and Triflates". The Journal of Organic Chemistry. 73 (18): 7380–7382. doi:10.1021/jo801063c. ISSN 0022-3263. PMID 18693766.

It was first published in 1979 by Akira Suzuki, and he shared the 2010 Nobel Prize in Chemistry with Richard F. Heck and Ei-ichi Negishi for their contribution to the discovery and development of palladium-catalyzed cross-couplings in organic synthesis.[4] This reaction is also known as the Suzuki–Miyaura reaction or simply as the Suzuki coupling. It is widely used to synthesize polyolefins, styrenes, and substituted biphenyls. Several reviews have been published describing advancements and the development of the Suzuki reaction.[5][6][7] The general scheme for the Suzuki reaction is shown below, where a carbon-carbon single bond is formed by coupling an organoboron species (R1-BY2) with a halide (R2-X) using a palladium catalyst and a base.

The mechanism of the Suzuki reaction is best viewed from the perspective of the palladium catalyst 1. The first step is the oxidative addition of palladium to the halide 2 to form the organopalladium species 3. Reaction (metathesis) with base gives intermediate 4, which via transmetalation[8] with the boron-ate complex 6 (produced by reaction of the boronic acid 5 with base) forms the organopalladium species 8. Reductive elimination of the desired product 9 restores the original palladium catalyst 1 which completes the catalytic cycle. The Suzuki coupling takes place in the presence of a base and for a long time the role of the base was not fully understood. The base was first believed to form a trialkyl borate (R3B-OR), in the case of a reaction of an trialkylborane (BR3) and alkoxide (−OR); this species could be considered as being more nucleophilic and then more reactive towards the palladium complex present in the transmetalation step.[9][10][11] Duc and coworkers investigated the role of the base in the reaction mechanism for the Suzuki coupling and they found that the base has three roles: Formation of the palladium complex [ArPd(OR)L2], formation of the trialkyl borate and the acceleration of the reductive elimination step by reaction of the alkoxide with the palladium complex.[9]

In most cases the oxidative addition is the rate determining step of the catalytic cycle.[12] During this step, the palladium catalyst is oxidized from palladium(0) to palladium(II). The palladium catalyst 1 is coupled with the alkyl halide 2 to yield an organopalladium complex 3. As seen in the diagram below, the oxidative addition step breaks the carbon-halogen bond where the palladium is now bound to both the halogen and the R group.

Oxidative addition proceeds with retention of stereochemistry with vinyl halides, while giving inversion of stereochemistry with allylic and benzylic halides.[13] The oxidative addition initially forms the cis–palladium complex, which rapidly isomerizes to the trans-complex.[14]

The Suzuki Coupling occurs with retention of configuration on the double bonds for both the organoboron reagent or the halide.[15] However, the configuration of that double bond, cis or trans is determined by the cis-to-trans isomerization of the palladium complex in the oxidative addition step where the trans palladium complex is the predominant form. When the organoboron is attached to a double bond and it is coupled to an alkenyl halide the product is a diene as shown below.

Transmetalation is an organometallic reaction where ligands are transferred from one species to another. In the case of the Suzuki coupling the ligands are transferred from the organoboron species 6 to the palladium(II) complex 4 where the base that was added in the prior step is exchanged with the R1 substituent on the organoboron species to give the new palladium(II) complex 8. The exact mechanism of transmetalation for the Suzuki coupling remains to be discovered. The organoboron compounds do not undergo transmetalation in the absence of base and it is therefore widely believed that the role of the base is to activate the organoboron compound as well as facilitate the formation of R2-Pdll-OtBu from R2-Pdll-X.[12]

The final step is the reductive elimination step where the palladium(II) complex (8) eliminates the product (9) and regenerates the palladium(0) catalyst(1). Using deuterium labelling, Ridgway et al. have shown the reductive elimination proceeds with retention of stereochemistry.[16]

The ligand plays an important role in the Suzuki reaction. Typically, the phosphine ligand is used in the Suzuki reaction. Phosphine ligand increases the electron density at the metal center of the complex and therefore helps in the oxidative addition step. In addition, the bulkiness of substitution of the phosphine ligand helps in the reductive elimination step. However, N-heterocyclic carbenes ligand has recently been used in this cross coupling, due to the instability of the phosphine ligand under Suzuki reaction conditions.[17] N-Heterocyclic carbenes are more electron rich and more bulkier than the phosphine ligand. Therefore, both the steric and electronic factors of the N-heterocyclic carbene ligand help to stabilize active Pd(0) catalyst.[18]

The advantages of Suzuki coupling over other similar reactions include availability of common boronic acids, mild reaction conditions, and its less toxic nature. Boronic acids are less toxic and safer for the environment than organotin and organozinc compounds. It is easy to remove the inorganic by-products from the reaction mixture. Further, this reaction is preferable because it uses relatively cheap and easily prepared reagents. Being able to use water as a solvent[19] makes this reaction more economical, eco-friendly, and practical to use with a variety of water-soluble reagents. A wide variety of reagents can be used for the Suzuki coupling, e.g., aryl- or vinyl-boronic acids and aryl- or vinyl-halides. Work has also extended the scope of the reaction to incorporate alkyl bromides.[20] In addition to many different type of halides being possible for the Suzuki coupling reaction, the reaction also works with pseudohalides such as triflates (OTf), as replacements for halides. The relative reactivity for the coupling partner with the halide or pseudohalide is: R2–I > R2–OTf > R2–Br >> R2–Cl. Boronic esters and organotrifluoroborate salts may be used instead of boronic acids. The catalyst can also be a palladium nanomaterial-based catalyst.[21] With a novel organophosphine ligand (SPhos), a catalyst loading of down to 0.001 mol% has been reported:.[22] These advances and the overall flexibility of the process have made the Suzuki coupling widely accepted for chemical synthesis.

The Suzuki coupling reaction is scalable and cost-effective for use in the synthesis of intermediates for pharmaceuticals or fine chemicals.[23] The Suzuki reaction was once limited by high levels of catalyst and the limited availability of boronic acids. Replacements for halides were also found, increasing the number of coupling partners for the halide or pseudohalide as well. Scaled up reactions have been carried out in the synthesis of a number of important biological compounds such as CI-1034 which used a triflate and boronic acid coupling partners which was run on an 80 kilogram scale with a 95% yield.[24]

Another example is the coupling of 3-pyridylborane and 1-bromo-3-(methylsulfonyl)benzene that formed an intermediate that was used in the synthesis of a potential central nervous system agent. The coupling reaction to form the intermediate produced (278 kilograms) in a 92.5% yield.[15][23]

Significant efforts have been put into the development of heterogeneous catalysts for the Suzuki CC reaction, motivated by the performance gains in the industrial process (eliminating the catalyst separation from the substrate), and recently a Pd single atom hetereogeneous catalyst has been shown to outperform the industry default homogeneous Pd(PPh3)4 catalyst.[25]

The Suzuki coupling has been frequently used in syntheses of complex compounds.[26][27] The Suzuki coupling has been used on a citronellal derivative for the synthesis of caparratriene, a natural product that is highly active against leukemia:[28]

Various catalytic uses of metals other than palladium (especially nickel) have been developed.[29] The first nickel catalyzed cross-coupling reaction was reported by Percec and co-workers in 1995 using aryl mesylates and boronic acids.[30] Even though a higher amount of nickel catalyst was needed for the reaction, around 5 mol %, nickel is not as expensive or as precious a metal as palladium. The nickel catalyzed Suzuki coupling reaction also allowed a number of compounds that did not work or worked worse for the palladium catalyzed system than the nickel-catalyzed system.[29] The use of nickel catalysts has allowed for electrophiles that proved challenging for the original Suzuki coupling using palladium, including substrates such as phenols, aryl ethers, esters, phosphates, and fluorides.[29]

Investigation into the nickel catalyzed cross-coupling continued and increased the scope of the reaction after these first examples were shown and the research interest grew. Miyaura and Inada reported in 2000 that a cheaper nickel catalyst could be utilized for the cross-coupling, using triphenylphosphine (PPh3) instead of the more expensive ligands previously used.[31] However, the nickel-catalyzed cross-coupling still required high catalyst loadings (3-10%), required excess ligand (1-5 equivalents) and remained sensitive to air and moisture.[29] Advancements by Han and co-workers have tried to address that problem by developing a method using low amounts of nickel catalyst (<1 mol%) and no additional equivalents of ligand.[32]

It was also reported by Wu and co-workers in 2011 that a highly active nickel catalyst for the cross-coupling of aryl chlorides could be used that only required 0.01-0.1 mol% of nickel catalyst. They also showed that the catalyst could be recycled up to six times with virtually no loss in catalytic activity.[33] The catalyst was recyclable because it was a phosphine nickel nanoparticle catalyst (G3DenP-Ni) that was made from dendrimers.

Advantages and disadvantages apply to both the palladium and nickel-catalyzed Suzuki coupling reactions. Apart from Pd and Ni catalyst system, cheap and non-toxic metal sources like iron and copper[34] have been used in Suzuki coupling reaction. The Bedford research group[35] and the Nakamura research group[36] have extensively worked on developing the methodology of iron catalyzed Suzuki coupling reaction. Ruthenium is another metal source that has been used in Suzuki coupling reaction.[37]

Nickel catalysis can construct C-C bonds from amides. Despite the inherently inert nature of amides as synthons, the following methodology can be used to prepare C-C bonds. The coupling procedure is mild and tolerant of myriad functional groups, including: amines, ketones, heterocycles, groups with acidic protons. This technique can also be used to prepare bioactive molecules and to unite heterocycles in controlled ways through shrewd sequential cross-couplings. A general review of the reaction scheme is given below.[38]

The synthesis of the tubulin binding compound (antiproliferative agent) was carried out using trimethoxyamide and a heterocyclic fragment.[38]

Aryl boronic acids are comparatively cheaper than other organoboranes and a wide variety of aryl boronic acids are commercially available. Hence, it has been widely used in Suzuki reaction as an organoborane partner. Aryltrifluoroborate salts are another class of organoboranes that are frequently used because they are less prone to protodeboronation compared to aryl boronic acids. They are easy to synthesize and can be easily purified.[39] Aryltrifluoroborate salts can be formed from boronic acids by the treatment with potassium hydrogen fluoride which can then be used in the Suzuki coupling reaction.[40]

The Suzuki coupling reaction is different from other coupling reactions in that it can be run in biphasic organic-water,[41] water-only,[19] or no solvent.[42] This increased the scope of coupling reactions, as a variety of water-soluble bases, catalyst systems, and reagents could be used without concern over their solubility in organic solvent. Use of water as a solvent system is also attractive because of the economic and safety advantages. Frequently used in solvent systems for Suzuki coupling are toluene,[43] THF,[44] dioxane,[44] and DMF.[45] The most frequently used bases are K2CO3,[41] KOtBu,[46] Cs2CO3,[47] K3PO4,[48] NaOH,[49] and NEt3.[50]

Chan-Lam coupling

Heck reaction

Hiyama coupling

Kumada coupling

Negishi coupling

Petasis reaction

Sonogashira coupling

Stille reaction

List of organic reactions

1. Miyaura, Norio; Yamada, Kinji; Suzuki, Akira (1979). "A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides". Tetrahedron Letters. 20 (36): 3437–3440. doi:10.1016/S0040-4039(01)95429-2. hdl:2115/44006.
2. Miyaura, Norio; Suzuki, Akira (1979). "Stereoselective synthesis of arylated (E)-alkenes by the reaction of alk-1-enylboranes with aryl halides in the presence of palladium catalyst". Chem. Comm. (19): 866–867. doi:10.1039/C39790000866.
3. Miyaura, Norio; Suzuki, Akira (1995). "Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds". Chemical Reviews. 95 (7): 2457–2483. CiteSeerX 10.1.1.735.7660. doi:10.1021/cr00039a007.
4. Nobelprize.org. "The Nobel Prize in Chemistry 2010". Nobel Prize Foundation. Retrieved 2013-10-25.
5. Suzuki, Akira (1991). "Synthetic Studies via the cross-coupling reaction of organoboron derivatives with organic halides". Pure Appl. Chem. 63 (3): 419–422. doi:10.1351/pac199163030419.
6. Miyaura, Norio; Suzuki, Akira (1979). "Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds". Chemical Reviews. 95 (7): 2457–2483. CiteSeerX 10.1.1.735.7660. doi:10.1021/cr00039a007.(Review)
7. Suzuki, Akira (1999). "Recent advances in the cross-coupling reactions of organoboron derivatives with organic electrophiles, 1995–1998". Journal of Organometallic Chemistry. 576 (1–2): 147–168. doi:10.1016/S0022-328X(98)01055-9.
8. Matos, K.; Soderquist, J. A. (1998). "Alkylboranes in the Suzuki−Miyaura Coupling: Stereochemical and Mechanistic Studies". J. Org. Chem. 63 (3): 461–470. doi:10.1021/jo971681s. PMID 11672034.
9. Amatore, Christian; Jutand, Anny; Le Duc, Gaëtan (18 February 2011). "Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki-Miyaura Reactions: Unexpected Triple Role of Hydroxide Ions Used as Base". Chemistry: A European Journal. 17 (8): 2492–2503. doi:10.1002/chem.201001911. PMID 21319240.
10. Smith, George B.; Dezeny, George C.; Hughes, David L.; King, Anthony O.; Verhoeven, Thomas R. (1 December 1994). "Mechanistic Studies of the Suzuki Cross-Coupling Reaction". The Journal of Organic Chemistry. 59 (26): 8151–8156. doi:10.1021/jo00105a036.
11. Matos, Karl; Soderquist, John A. (1 February 1998). "Alkylboranes in the Suzuki−Miyaura Coupling: Stereochemical and Mechanistic Studies". The Journal of Organic Chemistry. 63 (3): 461–470. doi:10.1021/jo971681s. PMID 11672034.
12. Kurti, Laszlo (2005). Strategic Applications of Named Reactions in Organic Synthesis. Elsevier Academic Press. ISBN 978-0124297852.
13. Stille, John K.; Lau, Kreisler S. Y. (1977). "Mechanisms of oxidative addition of organic halides to Group 8 transition-metal complexes". Accounts of Chemical Research. 10 (12): 434–442. doi:10.1021/ar50120a002.
14. Casado, Arturo L.; Espinet, Pablo (1998). "On the Configuration Resulting from Oxidative Addition of RX to Pd(PPh3)4and the Mechanism of thecis-to-transIsomerization of \PdRX(PPh3)2] Complexes (R = aryl, X = halide)†". Organometallics. 17 (5): 954–959. doi:10.1021/om9709502.
15. Advanced Organic Chemistry. Springer. 2007. pp. 739–747.
16. Ridgway, Brian H.; Woerpel, K. A. (1998). "Transmetalation of Alkylboranes to Palladium in the Suzuki Coupling Reaction Proceeds with Retention of Stereochemistry". The Journal of Organic Chemistry. 63 (3): 458–460. doi:10.1021/jo970803d. PMID 11672033.
17. "Science of Synthesis: Best methods. Best results – Thieme Chemistry". science-of-synthesis.thieme.com. Retrieved 2021-04-14.
18. Hopkinson, Matthew N.; Richter, Christian; Schedler, Michael; Glorius, Frank (June 2014). "An overview of N-heterocyclic carbenes". Nature. 510 (7506): 485–496. doi:10.1038/nature13384. ISSN 1476-4687.
19. Casalnuovo, Albert L.; Calabrese (1990). "Palladium-catalyzed alkylations in aqueous media". J. Am. Chem. Soc. 112 (11): 4324–4330. doi:10.1021/ja00167a032.
20. Kirchhoff, Jan H.; Netherton, Matthew R.; Hills, Ivory D.; Fu, Gregory C. (2002). "Boronic Acids: New Coupling Partners in Room-Temperature Suzuki Reactions of Alkyl Bromides. Crystallographic Characterization of an Oxidative-Addition Adduct Generated under Remarkably Mild Conditions". Journal of the American Chemical Society. 124 (46): 13662–3. doi:10.1021/ja0283899. PMID 12431081.
21. Ohtaka, Atsushi (2013). "Recyclable Polymer-Supported Nanometal Catalysts in Water". The Chemical Record. 13 (3): 274–285. doi:10.1002/tcr.201300001. PMID 23568378.
22. Martin, R.; Buchwald, S. L. (2008). "Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands". Accounts of Chemical Research. 41 (11): 1461–1473. doi:10.1021/ar800036s. PMC 2645945. PMID 18620434.
23. Rouhi, A. Maureen (6 September 2004). "Fine Chemicals". C&EN.
24. Jacks1, Thomas E.; Belmont, Daniel T.; Briggs, Christopher A.; Horne, Nicole M.; Kanter, Gerald D.; Karrick, Greg L.; Krikke, James J.; McCabe, Richard J.; Mustakis; Nanninga, Thomas N. (1 March 2004). "Development of a Scalable Process for CI-1034, an Endothelin Antagonist". Organic Process Research & Development. 8 (2): 201–212. doi:10.1021/op034104g.
25. Chen, Zupeng; Vorobyeva, Evgeniya; Mitchell, Sharon; Fako, Edvin; Ortuño, Manuel A.; López, Núria; Collins, Sean M.; Midgley, Paul A.; Richard, Sylvia; Vilé, Gianvito; Pérez-Ramírez, Javier (2018). "A heterogeneous single-atom palladium catalyst surpassing homogeneous systems for Suzuki coupling" (PDF). Nature Nanotechnology. 13 (8): 702–707. doi:10.1038/s41565-018-0167-2. hdl:2072/359786. PMID 29941887. S2CID 49415437.
26. Balog, Aaron; Meng, Dongfang; Kamenecka, Ted; Bertinato, Peter; Su, Dai-Shi; Sorensen, Erik J.; Danishefsky, Samuel J. (1996). "Total Synthesis of(–)-Epothilone A". Angewandte Chemie International Edition in English. 35 (2324): 2801–2803. doi:10.1002/anie.199628011.
27. Liu, Junjia; Lotesta, Stephen D.; Sorensen, Erik J. (2011). "A concise synthesis of the molecular framework of pleuromutilin". Chemical Communications. 47 (5): 1500–2. doi:10.1039/C0CC04077K. PMC 3156455. PMID 21079876.
28. Vyvyan, J. R.; Peterson, Emily A.; Stephan, Mari L. (1999). "An expedient total synthesis of (+/−)-caparratriene". Tetrahedron Letters. 40 (27): 4947–4949. doi:10.1016/S0040-4039(99)00865-5.
29. Han, Fu-She (1 January 2013). "Transition-metal-catalyzed Suzuki–Miyaura cross-coupling reactions: a remarkable advance from palladium to nickel catalysts". Chemical Society Reviews. 42 (12): 5270–98. doi:10.1039/c3cs35521g. PMID 23460083.
30. Percec, Virgil; Bae, Jin-Young; Hill, Dale (1995). "Aryl Mesylates in Metal Catalyzed Homocoupling and Cross-Coupling Reactions. 2. Suzuki-Type Nickel-Catalyzed Cross-Coupling of Aryl Arenesulfonates and Aryl Mesylates with Arylboronic Acids". Journal of Organic Chemistry. 60 (4): 1060–1065. doi:10.1021/jo00109a044.
31. Inada, Kaoru; Norio Miyaura (2000). "Synthesis of Biaryls via Cross-Coupling Reaction of Arylboronic Acids with Aryl Chlorides Catalyzed by NiCl2/Triphenylphosphine Complexes". Tetrahedron. 56 (44): 8657–8660. doi:10.1016/S0040-4020(00)00814-0.
32. Zhao, Yu-Long; Li, You; Li, Shui-Ming; Zhou, Yi-Guo; Sun, Feng-Yi; Gao, Lian-Xun; Han, Fu-She (1 June 2011). "A Highly Practical and Reliable Nickel Catalyst for Suzuki-Miyaura Coupling of Aryl Halides". Advanced Synthesis & Catalysis. 353 (9): 1543–1550. doi:10.1002/adsc.201100101.
33. Wu, Lei; Ling, Jie; Wu, Zong-Quan (1 June 2011). "A Highly Active and Recyclable Catalyst: Phosphine Dendrimer-Stabilized Nickel Nanoparticles for the Suzuki Coupling Reaction". Advanced Synthesis & Catalysis. 353 (9): 1452–1456. doi:10.1002/adsc.201100134.
34. Yang, C.T.; Zhang, Zhen-Qi; Liu, Yu-Chen; Liu, Lei (2011). "Copper-Catalyzed Cross-Coupling Reaction of Organoboron Compounds with Primary Alkyl Halides and Pseudohalides". Angew. Chem. Int. Ed. 50 (17): 3904–3907. doi:10.1002/anie.201008007. PMID 21455914.
35. Bredford, R.B.; Hall, Mark A.; Hodges, George R.; Huwe, Michael; Wilkinson, Mark C. (2009). "Simple mixed Fe–Zn catalysts for the Suzuki couplings of tetraarylborates with benzyl halides and 2-halopyridines". Chem. Commun. (42): 6430–6432. doi:10.1039/B915945B. PMID 19841799. S2CID 40428708.
36. Nakamura, M; Hashimoto, Toru; Kathriarachchi, Kalum K. A. D. S.; Zenmyo, Takeshi; Seike, Hirofumi; Nakamura, Masaharu (2012). "Iron-Catalyzed Alkyl-Alkyl Suzuki-Miyaura Coupling". Angew. Chem. Int. Ed. 51 (35): 8834–883. doi:10.1002/anie.201202797. PMID 22848024.
37. Na, Y; Park, Soyoung; Han, Soo Bong; Han, Hoon; Ko, Sangwon; Chang, Sukbok (2004). "Ruthenium-Catalyzed Heck-Type Olefination and Suzuki Coupling Reactions: Studies on the Nature of Catalytic Species". J. Am. Chem. Soc. 126 (1): 250–258. doi:10.1021/ja038742q. PMID 14709090.
38. Weires, Nicholas A.; Baker, Emma L.; Garg, Neil K. (2015). "Nickel-catalysed Suzuki–Miyaura coupling of amides". Nature Chemistry. 8 (1): 75–79. Bibcode:2016NatCh...8...75W. doi:10.1038/nchem.2388. PMID 26673267.
39. Molander, Gary A.; Biolatto, Betina (2003). "Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions of Potassium Aryl- and Heteroaryltrifluoroborates". J. Org. Chem. 68 (11): 4302–4314. doi:10.1021/jo0342368. PMID 12762730.
40. Bates, Roderick (2012). Organic Synthesis Using Transition Metals. Wiley. ISBN 978-1119978930.
41. Dolliver, Debra; Bhattarai, Bijay T.; Pandey, Arjun; Lanier, Megan L.; Bordelon, Amber S.; Adhikari, Sarju; Dinser, Jordan A.; Flowers, Patrick F.; Wills, Veronica S.; Schneider, Caroline L.; Shaughnessy, Kevin H.; Moore, Jane N.; Raders, Steven M.; Snowden, Timothy S.; McKim, Artie S.; Fronczek, Frank R. (2013). "Stereospecific Suzuki, Sonogashira, and Negishi Coupling Reactions of N-Alkoxyimidoyl Iodides and Bromides". J. Org. Chem. 78 (8): 3676–3687. doi:10.1021/jo400179u. PMID 23534335.
42. Asachenko, Andrey; Sorochkina, Kristina; Dzhevakov, Pavel; Topchiy, Maxim; Nechaev, Mikhail (2013). "Suzuki–Miyaura Cross-Coupling under Solvent-Free Conditions". Adv. Synth. Catal. 355 (18): 3553–3557. doi:10.1002/adsc.201300741.
43. Pan, Changduo; Liu, Zhang; Wu, Huayue; Din, Jinchang; Cheng, Jiang (2008). "Palladium catalyzed ligand-free Suzuki cross-coupling reaction". Catalysis Communications. 9 (4): 321–323. doi:10.1016/j.catcom.2007.06.022.
44. Littke, Adam F.; Fu (2000). "Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions". J. Am. Chem. Soc. 122 (17): 4020–4028. doi:10.1021/ja0002058.
45. Hu, Ming-Gang; Wei, Song; Jian, Ai-Ai (2007). "Highly Efficient Pd/C-Catalyzed Suzuki Coupling Reaction ofp-(un)Substituted Phenyl Halide with (p-Substituted phenyl) Boronic Acid". Chinese Journal of Chemistry. 25 (8): 1183–1186. doi:10.1002/cjoc.200790220.
46. Saito, B; Fu (2007). "Alkyl−Alkyl Suzuki Cross-Couplings of Unactivated Secondary Alkyl Halides at Room Temperature". J. Am. Chem. Soc. 129 (31): 9602–9603. doi:10.1021/ja074008l. PMC 2569998. PMID 17628067.
47. Kingston, J.V.; Verkade, John G. (2007). "Synthesis and Characterization of R2PNP(iBuNCH2CH2)3N: A New Bulky Electron-Rich Phosphine for Efficient Pd-Assisted Suzuki−Miyaura Cross-Coupling Reactions". J. Org. Chem. 72 (8): 2816–2822. doi:10.1021/jo062452l. PMID 17378611.
48. Baillie, C; Zhang, Lixin; Xiao, Jianliang (2004). "Ferrocenyl Monophosphine Ligands: Synthesis and Applications in the Suzuki−Miyaura Coupling of Aryl Chlorides". J. Org. Chem. 69 (22): 7779–7782. doi:10.1021/jo048963u. PMID 15498017.
49. Han, J; Liu, Y; Guo, R (2009). "Facile synthesis of highly stable gold nanoparticles and their unexpected excellent catalytic activity for Suzuki-Miyaura cross-coupling reaction in water". J. Am. Chem. Soc. 131 (6): 2060–2061. doi:10.1021/ja808935n. PMID 19170490.
50. Lipshutz, B.H.; Petersen, Tue B.; Abela, Alexander R. (2008). "Room-Temperature Suzuki−Miyaura Couplings in Water Facilitated by Nonionic Amphiphiles†". Org. Lett. 10 (7): 1333–1336. doi:10.1021/ol702714y. PMID 18335944.

The reaction involves the coupling of two organic groups, one of which is carried as an organotin compound (also known as organostannanes). A variety of organic electrophiles provide the other coupling partner. The Stille reaction is one of many palladium-catalyzed coupling reactions.[1][2][3]

The R1 group attached to the trialkyltin is normally sp2-hybridized, including vinyl, and aryl groups.

These organostannanes are also stable to both air and moisture, and many of these reagents either are commercially available or can be synthesized from literature precedent. However, these tin reagents tend to be highly toxic. X is typically a halide, such as Cl, Br, or I, yet pseudohalides such as triflates and sulfonates and phosphates can also be used.[4][5] Several reviews have been published.[6][2][7][8][9][10][11][12][13][14][15]

The first example of a palladium catalyzed coupling of aryl halides with organotin reagents was reported by Colin Eaborn in 1976.[16] This reaction yielded from 7% to 53% of diaryl product. This process was expanded to the coupling of acyl chlorides with alkyl-tin reagents in 1977 by Toshihiko Migita, yielding 53% to 87% ketone product.[17]

In 1977, Migita published further work on the coupling of allyl-tin reagents with both aryl (C) and acyl (D) halides. The greater ability of allyl groups to migrate to the palladium catalyst allowed the reactions to be performed at lower temperatures. Yields for aryl halides ranged from 4% to 100%, and for acyl halides from 27% to 86%.[18][19] Reflecting the early contributions of Migita and Kosugi, the Stille reaction is sometimes called the Migita–Kosugi–Stille coupling.

John Kenneth Stille subsequently reported the coupling of a variety of alkyl tin reagents in 1978 with numerous aryl and acyl halides under mild reaction conditions with much better yields (76%-99%).[18][20] Stille continued his work in the 1980s on the synthesis of a multitude of ketones using this broad and mild process and elucidated a mechanism for this transformation.[21][22]

By the mid-1980s, over 65 papers on the topic of coupling reactions involving tin had been published, continuing to explore the substrate scope of this reaction. While initial research in the field focused on the coupling of alkyl groups, most future work involved the much more synthetically useful coupling of vinyl, alkenyl, aryl, and allyl organostannanes to halides. Due to these organotin reagent's stability to air and their ease of synthesis, the Stille reaction became common in organic synthesis.[8]

The mechanism of the Stille reaction has been extensively studied.[11][23] The catalytic cycle involves an oxidative addition of a halide or pseudohalide (2) to a palladium catalyst (1), transmetalation of 3 with an organotin reagent (4), and reductive elimination of 5 to yield the coupled product (7) and the regenerated palladium catalyst (1).[24]

However, the detailed mechanism of the Stille coupling is extremely complex and can occur via numerous reaction pathways. Like other palladium-catalyzed coupling reactions, the active palladium catalyst is believed to be a 14-electron Pd(0) complex, which can be generated in a variety of ways. Use of an 18- or 16- electron Pd(0) source Pd(PPh3)4, Pd(dba)2 can undergo ligand dissociation to form the active species. Second, phosphines can be added to ligandless palladium(0). Finally, as pictured, reduction of a Pd(II) source (8) (Pd(OAc)2, PdCl2(MeCN)2, PdCl2(PPh3)2, BnPdCl(PPh3)2, etc.) by added phosphine ligands or organotin reagents is also common [6]

Oxidative addition to the 14-electron Pd(0) complex is proposed. This process gives a 16-electron Pd(II) species. It has been suggested that anionic ligands, such as OAc, accelerate this step by the formation of [Pd(OAc)(PR3)n]−, making the palladium species more nucleophillic.[11][25] In some cases, especially when an sp3-hybridized organohalide is used, an SN2 type mechanism tends to prevail, yet this is not as commonly seen in the literature.[11][25] However, despite normally forming a cis-intermediate after a concerted oxidative addition, this product is in rapid equilibrium with its trans-isomer.[26][27]

There are multiple reasons why isomerization is favored here. First, a bulky ligand set is usually used in these processes, such as phosphines, and it is highly unfavorable for them to adopt a cis orientation relative to each other, resulting in isomerization to the more favorable trans product.[26][27] An alternative explanation for this phenomenon, dubbed antisymbiosis or transphobia, is by invocation of the sdn model.[24][28] Under this theory, palladium is a hypervalent species. Hence R1 and the trans ligand, being trans to each other, will compete with one palladium orbital for bonding. This 4-electron 3-center bond is weakest when two strong donating groups are present, which heavily compete for the palladium orbital. Relative to any ligand normally used, the C-donor R1 ligand has a much higher trans effect. This trans influence is a measure of how competitive ligands trans to each other will compete for palladium's orbital. The usual ligand set, phosphines, and C-donors (R1) are both soft ligands, meaning that they will form strong bonds to palladium, and heavily compete with each other for bonding.[29][30] Since halides or pseudohalides are significantly more electronegative, their bonding with palladium will be highly polarized, with most of the electron density on the X group, making them low trans effect ligands. Hence, it will be highly favorable for R1 to be trans to X, since the R1 group will be able to form a stronger bond to the palladium.[24][28][30]

The transmetalation of the trans intermediate from the oxidative addition step is believed to proceed via a variety of mechanisms depending on the substrates and conditions. The most common type of transmetalation for the Stille coupling involves an associative mechanism. This pathway implies that the organostannane, normally a tin atom bonded to an allyl, alkenyl, or aryl group, can coordinate to the palladium via one of these double bonds. This produces a fleeting pentavalent, 18-electron species, which can then undergo ligand detachment to form a square planar complex again. Despite the organostannane being coordinated to the palladium through the R2 group, R2 must be formally transferred to the palladium (the R2-Sn bond must be broken), and the X group must leave with the tin, completing the transmetalation. This is believed to occur through two mechanisms.[31]

First, when the organostannane initially adds to the trans metal complex, the X group can coordinate to the tin, in addition to the palladium, producing a cyclic transition state. Breakdown of this adduct results in the loss of R3Sn-X and a trivalent palladium complex with R1 and R2 present in a cis relationship. Another commonly seen mechanism involves the same initial addition of the organostannane to the trans palladium complex as seen above; however, in this case, the X group does not coordinate to the tin, producing an open transition state. After the α-carbon relative to tin attacks the palladium, the tin complex will leave with a net positive charge. In the scheme below, please note that the double bond coordinating to tin denotes R2, so any alkenyl, allyl, or aryl group. Furthermore, the X group can dissociate at any time during the mechanism and bind to the Sn+ complex at the end. Density functional theory calculations predict that an open mechanism will prevail if the 2 ligands remain attached to the palladium and the X group leaves, while the cyclic mechanism is more probable if a ligand dissociates prior to the transmetalation. Hence, good leaving groups such as triflates in polar solvents favor the former, while bulky phosphine ligands will favor the latter.[31]

A less common pathway for transmetalation is through a dissociative or solvent assisted mechanism. Here, a ligand from the tetravalent palladium species dissociates, and a coordinating solvent can add onto the palladium. When the solvent detaches, to form a 14-electron trivalent intermediate, the organostannane can add to the palladium, undergoing an open or cyclic type process as above.[31]

In order for R1-R2 to reductively eliminate, these groups must occupy mutually cis coordination sites. Any trans-adducts must therefore isomerize to the cis intermediate or the coupling will be frustrated. A variety of mechanisms exist for reductive elimination and these are usually considered to be concerted.[11][32][33]

First, the 16-electron tetravalent intermediate from the transmetalation step can undergo unassisted reductive elimination from a square planar complex. This reaction occurs in two steps: first, the reductive elimination is followed by coordination of the newly formed sigma bond between R1 and R2 to the metal, with ultimate dissociation yielding the coupled product.[11][32][33]

The previous process, however, is sometimes slow and can be greatly accelerated by dissociation of a ligand to yield a 14-electron T shaped intermediate. This intermediate can then rearrange to form a Y-shaped adduct, which can undergo faster reductive elimination.[11][32][33]

Finally, an extra ligand can associate to the palladium to form an 18-electron trigonal bipyramidal structure, with R1 and R2 cis to each other in equatorial positions. The geometry of this intermediate makes it similar to the Y-shaped above.[11][32][33]

The presence of bulky ligands can also increase the rate of elimination. Ligands such as phosphines with large bite angles cause steric repulsion between L and R1 and R2, resulting in the angle between L and the R groups to increase and the angle between R1 and R2 to hence decrease, allowing for quicker reductive elimination.[11][24]

The rate at which organostannanes transmetalate with palladium catalysts is shown below. Sp2-hybridized carbon groups attached to tin are the most commonly used coupling partners, and sp3-hybridized carbons require harsher conditions and terminal alkynes may be coupled via a C-H bond through the Sonogashira reaction.

As the organic tin compound, a trimethylstannyl or tributylstannyl compound is normally used. Although trimethylstannyl compounds show higher reactivity compared with tributylstannyl compounds and have much simpler 1H-NMR spectra, the toxicity of the former is much larger.[34]

Optimizing which ligands are best at carrying out the reaction with high yield and turnover rate can be difficult. This is because the oxidative addition requires an electron rich metal, hence favoring electron donating ligands. However, an electron deficient metal is more favorable for the transmetalation and reductive elimination steps, making electron withdrawing ligands the best here. Therefore, the optimal ligand set heavily depends on the individual substrates and conditions used. These can change the rate determining step, as well as the mechanism for the transmetalation step.[35]

Normally, ligands of intermediate donicity, such as phosphines, are utilized. Rate enhancements can be seen when moderately electron-poor ligands, such as tri-2-furylphosphine or triphenylarsenine are used. Likewise, ligands of high donor number can slow down or inhibit coupling reactions.[35][36]

These observations imply that normally, the rate-determining step for the Stille reaction is transmetalation.[36]

The most common additive to the Stille reaction is stoichiometric or co-catalytic copper(I), specifically copper iodide, which can enhance rates up by >103 fold. It has been theorized that in polar solvents copper transmetalate with the organostannane. The resulting organocuprate reagent could then transmetalate with the palladium catalyst. Furthermore, in ethereal solvents, the copper could also facilitate the removal of a phosphine ligand, activating the Pd center.[9][37][38][39][40]

Lithium chloride has been found to be a powerful rate accelerant in cases where the X group dissociates from palladium (i.e. the open mechanism). The chloride ion is believed to either displace the X group on the palladium making the catalyst more active for transmetalation or by coordination to the Pd(0) adduct to accelerate the oxidative addition. Also, LiCl salt enhances the polarity of the solvent, making it easier for this normally anionic ligand (–Cl, –Br, –OTf, etc.) to leave. This additive is necessary when a solvent like THF is used; however, utilization of a more polar solvent, such as NMP, can replace the need for this salt additive. However, when the coupling's transmetalation step proceeds via the cyclic mechanism, addition of lithium chloride can actually decrease the rate. As in the cyclic mechanism, a neutral ligand, such as phosphine, must dissociate instead of the anionic X group.[10][41]

Finally, sources of fluoride ions, such as cesium fluoride, also effect on the catalytic cycle. First, fluoride can increase the rates of reactions of organotriflates, possibly by the same effect as lithium chloride. Furthermore, fluoride ions can act as scavengers for tin byproducts, making them easier to remove via filtration.[39]

The most common side reactivity associated with the Stille reaction is homocoupling of the stannane reagents to form an R2-R2 dimer. It is believed to proceed through two possible mechanisms. First, reaction of two equivalents of organostannane with the Pd(II) precatalyst will yield the homocoupled product after reductive elimination. Second, the Pd(0) catalyst can undergo a radical process to yield the dimer. The organostannane reagent used is traditionally tetravalent at tin, normally consisting of the sp2-hybridized group to be transferred and three "non-transferable" alkyl groups. As seen above, alkyl groups are normally the slowest at migrating onto the palladium catalyst.[10]

It has also been found that at temperatures as low as 50 °C, aryl groups on both palladium and a coordinated phosphine can exchange. While normally not detected, they can be a potential minor product in many cases.[10]

Finally, a rather rare and exotic side reaction is known as cine substitution. Here, after initial oxidative addition of an aryl halide, this Pd-Ar species can insert across a vinyl tin double bond. After β-hydride elimination, migratory insertion, and protodestannylation, a 1,2-disubstituted olefin can be synthesized.[10]

Numerous other side reactions can occur, and these include E/Z isomerization, which can potentially be a problem when an alkenylstannane is utilized. The mechanism of this transformation is currently unknown. Normally, organostannanes are quite stable to hydrolysis, yet when very electron-rich aryl stannanes are used, this can become a significant side reaction.[10]

Vinyl halides are common coupling partners in the Stille reaction, and reactions of this type are found in numerous natural product total syntheses. Normally, vinyl iodides and bromides are used. Vinyl chlorides are insufficiently reactive toward oxidative addition to Pd(0). Iodides are normally preferred: they will typically react faster and under milder conditions than will bromides. This difference is demonstrated below by the selective coupling of a vinyl iodide in the presence of a vinyl bromide.[10]

Normally, the stereochemistry of the alkene is retained throughout the reaction, except under harsh reaction conditions. A variety of alkenes may be used, and these include both α- and β-halo-α,β unsaturated ketones, esters, and sulfoxides (which normally need a copper (I) additive to proceed), and more (see example below).[42] Vinyl triflates are also sometimes used. Some reactions require the addition of LiCl and others are slowed down, implying that two mechanistic pathways are present.[10]

Another class of common electrophiles are aryl and heterocyclic halides. As for the vinyl substrates, bromides and iodides are more common despite their greater expense. A multitude of aryl groups can be chosen, including rings substituted with electron donating substituents, biaryl rings, and more. Halogen-substituted heterocycles have also been used as coupling partners, including pyridines, furans, thiophenes, thiazoles, indoles, imidazoles, purines, uracil, cytosines, pyrimidines, and more (See below for table of heterocycles; halogens can be substituted at a variety of positions on each).[10]

Below is an example of the use of Stille coupling to build complexity on heterocycles of nucleosides, such as purines.[43]

Aryl triflates and sulfonates are also couple to a wide variety of organostannane reagents. Triflates tend to react comparably to bromides in the Stille reaction.[10]

Acyl chlorides are also used as coupling partners and can be used with a large range of organostannane, even alkyl-tin reagents, to produce ketones (see example below).[44] However, it is sometimes difficult to introduce acyl chloride functional groups into large molecules with sensitive functional groups. An alternative developed to this process is the Stille-carbonylative cross-coupling reaction, which introduces the carbonyl group via carbon monoxide insertion.[10]

Allylic, benzylic, and propargylic halides can also be coupled. While commonly employed, allylic halides proceed via an η3 transition state, allowing for coupling with the organostannane at either the α or γ position, occurring predominantly at the least substituted carbon (see example below).[45] Alkenyl epoxides (adjacent epoxides and alkenes) can also undergo this same coupling through an η3 transition state as, opening the epoxide to an alcohol. While allylic and benzylic acetates are commonly used, propargylic acetates are unreactive with organostannanes.[10]

Organostannane reagents are common. Several are commercially available.[46] Stannane reagents can be synthesized by the reaction of a Grignard or organolithium reagent with trialkyltin chlorides. For example, vinyltributyltin is prepared by the reaction of vinylmagnesium bromide with tributyltin chloride.[47] Hydrostannylation of alkynes or alkenes provides many derivatives. Organotin reagents are air and moisture stable. Some reactions can even take place in water.[48] They can be purified by chromatography. They are tolerant to most functional groups. Some organotin compounds are heavily toxic, especially trimethylstannyl derivatives.[10]

The use of vinylstannane, or alkenylstannane reagents is widespread.[10] In regards to limitations, both very bulky stannane reagents and stannanes with substitution on the α-carbon tend to react sluggishly or require optimization. For example, in the case below, the α-substituted vinylstannane only reacts with a terminal iodide due to steric hindrance.[49]

Arylstannane reagents are also common and both electron donating and electron withdrawing groups actually increase the rate of the transmetalation. This again implies that two mechanisms of transmetalation can occur. The only limitation to these reagents are substituents at the ortho-position as small as methyl groups can decrease the rate of reaction. A wide variety of heterocycles (see Electrophile section) can also be used as coupling partners (see example with a thiazole ring below).[10][50]

Alkynylstannanes, the most reactive of stannanes, have also been used in Stille couplings. They are not usually needed as terminal alkynes can couple directly to palladium catalysts through their C-H bond via Sonogashira coupling. Allylstannanes have been reported to have worked, yet difficulties arise, like with allylic halides, with the difficulty in control regioselectivity for α and γ addition. Distannane and acyl stannane reagents have also been used in Stille couplings.[10]

The Stille reaction has been used in the synthesis of a variety of polymers.[51][52][53] However, the most widespread use of the Stille reaction is its use in organic syntheses, and specifically, in the synthesis of natural products.

Larry Overman's 19-step enantioselective total synthesis of quadrigemine C involves a double Stille cross metathesis reaction.[6][54] The complex organostannane is coupled onto two aryl iodide groups. After a double Heck cyclization, the product is achieved.

Panek's 32 step enantioselective total synthesis of ansamycin antibiotic (+)-mycotrienol makes use of a late stage tandem Stille type macrocycle coupling. Here, the organostannane has two terminal tributyl tin groups attacked to an alkene. This organostannane "stiches" the two ends of the linear starting material into a macrocycle, adding the missing two methylene units in the process. After oxidation of the aromatic core with ceric ammonium nitrate (CAN) and deprotection with hydrofluoric acid yields the natural product in 54% yield for the 3 steps.[6][55]

Stephen F. Martin and coworkers' 21 step enantioselective total synthesis of the manzamine antitumor alkaloid Ircinal A makes use of a tandem one-pot Stille/Diels-Alder reaction. An alkene group is added to vinyl bromide, followed by an in situ Diels-Alder cycloaddition between the added alkene and the alkene in the pyrrolidine ring.[6][56]

Numerous other total syntheses utilize the Stille reaction, including those of oxazolomycin,[57] lankacidin C,[58] onamide A,[59] calyculin A,[60] lepicidin A,[61] ripostatin A,[62] and lucilactaene.[6][63] The image below displays the final natural product, the organohalide (blue), the organostannane (red), and the bond being formed (green and circled). From these examples, it is clear that the Stille reaction can be used both at the early stages of the synthesis (oxazolomycin and calyculin A), at the end of a convergent route (onamide A, lankacidin C, ripostatin A), or in the middle (lepicidin A and lucilactaene). The synthesis of ripostatin A features two concurrent Stille couplings followed by a ring-closing metathesis. The synthesis of lucilactaene features a middle subunit, having a borane on one side and a stannane on the other, allowing for Stille reactionfollowed by a subsequent Suzuki coupling.

In addition to performing the reaction in a variety of organic solvents, conditions have been devised which allow for a broad range of Stille couplings in aqueous solvent.[14]

In the presence of Cu(I) salts, palladium-on-carbon has been shown to be an effective catalyst.[64][65]

In the realm of green chemistry a Stille reaction is reported taking place in a low melting and highly polar mixture of a sugar such as mannitol, a urea such as dimethylurea and a salt such as ammonium chloride[66] .[67] The catalyst system is tris(dibenzylideneacetone)dipalladium(0) with triphenylarsine:

A common alteration to the Stille coupling is the incorporation of a carbonyl group between R1 and R2, serving as an efficient method to form ketones. This process is extremely similar to the initial exploration by Migita and Stille (see History) of coupling organostannane to acyl chlorides. However, these moieties are not always readily available and can be difficult to form, especially in the presence of sensitive functional groups. Furthermore, controlling their high reactivity can be challenging. The Stille-carbonylative cross-coupling employs the same conditions as the Stille coupling, except with an atmosphere of carbon monoxide (CO) being used. The CO can coordinate to the palladium catalyst (9) after initial oxidative addition, followed by CO insertion into the Pd-R1 bond (10), resulting in subsequent reductive elimination to the ketone (12). The transmetalation step is normally the rate-determining step.[6]

Larry Overman and coworkers make use of the Stille-carbonylative cross-coupling in their 20-step enantioselective total synthesis of strychnine. The added carbonyl is later converted to a terminal alkene via a Wittig reaction, allowing for the key tertiary nitrogen and the pentacyclic core to be formed via an aza-Cope-Mannich reaction.[6][68]

Giorgio Ortar et al. explored how the Stille-carbonylative cross-coupling could be used to synthesize benzophenone phosphores. These were embedded into 4-benzoyl-L-phenylalanine peptides and used for their photoaffinity labelling properties to explore various peptide-protein interactions.[6][69]

Louis Hegedus' 16-step racemic total synthesis of Jatraphone involved a Stille-carbonylative cross-coupling as its final step to form the 11-membered macrocycle. Instead of a halide, a vinyl triflate is used there as the coupling partner.[6][70]

Using the seminal publication by Eaborn in 1976, which forms arylstannanes from arylhalides and distannanes, T. Ross Kelly applied this process to the intramolecular coupling of arylhalides. This tandem stannylation/aryl halide coupling was used for the syntheses of a variety of dihydrophenanthrenes. Most of the internal rings formed are limited to 5 or 6 members, however some cases of macrocyclization have been reported. Unlike a normal Stille coupling, chlorine does not work as a halogen, possibly due to its lower reactivity in the halogen sequence (its shorter bond length and stronger bond dissociation energy makes it more difficult to break via oxidative addition). Starting in the middle of the scheme below and going clockwise, the palladium catalyst (1) oxidatively adds to the most reactive C-X bond (13) to form 14, followed by transmetalation with distannane (15) to yield 16 and reductive elimination to yield an arylstannane (18). The regenerated palladium catalyst (1) can oxidative add to the second C-X bond of 18 to form 19, followed by intramolecular transmetalation to yield 20, followed by reductive elimination to yield the coupled product (22).[6]

Jie Jack Lie et al. made use of the Stille-Kelly coupling in their synthesis of a variety of benzo[4,5]furopyridines ring systems. They invoke a three-step process, involving a Buchwald-Hartwig amination, another palladium-catalyzed coupling reaction, followed by an intramolecular Stille-Kelly coupling. Note that the aryl-iodide bond will oxidatively add to the palladium faster than either of the aryl-bromide bonds.[6][71]

See also

Organotin chemistry

Organostannane addition

Palladium-catalyzed coupling reactions

Suzuki reaction

Negishi coupling

Heck reaction

Hiyama coupling

Heck was awarded the 2010 Nobel Prize in Chemistry, which he shared with Ei-ichi Negishi and Akira Suzuki, for the discovery and development of this reaction. This reaction was the first example of a carbon-carbon bond-forming reaction that followed a Pd(0)/Pd(II) catalytic cycle, the same catalytic cycle that is seen in other Pd(0)-catalyzed cross-coupling reactions. The Heck reaction is a way to substitute alkenes.[2][3][4][5]

The original reaction by Tsutomu Mizoroki (1971) describes the coupling between iodobenzene and styrene in methanol to form stilbene at 120 °C (autoclave) with potassium acetate base and palladium chloride catalysis. This work was an extension of earlier work by Fujiwara (1967) on the Pd(II)-mediated coupling of arenes (Ar–H) and alkenes[6][7] and earlier work by Heck (1969) on the coupling of arylmercuric halides (ArHgCl) with alkenes using a stoichiometric amount of a palladium(II) species.[8]

In 1972 Heck acknowledged the Mizoroki publication and detailed independently discovered work. The reaction conditions differ in catalyst used (palladium acetate) and catalyst loading (0.01 eq.), base used (a hindered amine) and lack of solvent.[9][10]

In these reactions the active catalyst Pd(0) (see reaction mechanism) is formed by Pd coordination to the alkene.

In 1974 Heck introduced phosphine ligands into the equation.[11]

The reaction is catalyzed by palladium salts and complexes. Typical catalysts and precatalysts include tetrakis(triphenylphosphine)palladium(0), palladium chloride, and palladium(II) acetate. Typical supporting ligands are triphenylphosphine, PHOX and BINAP. Typical bases are triethylamine, potassium carbonate, and sodium acetate.

The aryl electrophile can be a halide (Br, Cl) or a triflate as well as benzyl or vinyl halides. The alkene must contain at least one sp2-C-H bond. Electron-withdrawing substituents enhance the reaction, thus acrylates are ideal.[12]

The mechanism involves organopalladium intermediates. The palladium(0) compound required in this cycle is generated in situ from a palladium(II) precursor.[13][14]

For instance, palladium(II) acetate is reduced by triphenylphosphine to bis(triphenylphosphine)palladium(0) (1) and triphenylphosphine is oxidized to triphenylphosphine oxide. Step A is an oxidative addition in which palladium inserts itself in the aryl to bromide bond. Palladium then forms a π complex with the alkene (3) and in step B the alkene inserts itself in the palladium - carbon bond in a syn addition step. Then follows a torsional strain relieving rotation to the trans isomer (not shown) and step C is a beta-hydride elimination (here the arrows are showing the opposite) step with the formation of a new palladium - alkene π complex (5). This complex is destroyed in the next step. The palladium(0) compound is regenerated by reductive elimination of the palladium(II) compound by potassium carbonate in the final step, D. In the course of the reaction the carbonate is stoichiometrically consumed and palladium is truly a catalyst and used in catalytic amounts. A similar palladium cycle but with different scenes and actors is observed in the Wacker process.

This cycle is not limited to vinyl compounds, in the Sonogashira coupling one of the reactants is an alkyne and in the Suzuki coupling the alkene is replaced by an aryl boronic acid and in the Stille reaction by an aryl stannane. The cycle also extends to the other group 10 element nickel for example in the Negishi coupling between aryl halides and organozinc compounds. Platinum forms strong bonds with carbon and does not have a catalytic activity in this type of reaction.

This coupling reaction is stereoselective with a propensity for trans coupling as the palladium halide group and the bulky organic residue move away from each other in the reaction sequence in a rotation step. The Heck reaction is applied industrially in the production of naproxen and the sunscreen component octyl methoxycinnamate. The naproxen synthesis includes a coupling between a brominated naphthalene compound with ethylene:[15]

In the presence of an ionic liquid a Heck reaction proceeds in absence of a phosphorus ligand. In one modification palladium acetate and the ionic liquid (bmim)PF6 are immobilized inside the cavities of reversed-phase silica gel.[16] In this way the reaction proceeds in water and the catalyst is re-usable.

In the Heck oxyarylation modification the palladium substituent in the syn-addition intermediate is displaced by a hydroxyl group and the reaction product contains a dihydrofuran ring.[17]

In the amino-Heck reaction a nitrogen to carbon bond is formed. In one example,[18] an oxime with a strongly electron withdrawing group reacts intramolecularly with the end of a diene to form a pyridine compound. The catalyst is tetrakis(triphenylphosphine)palladium(0) and the base is triethylamine.

Hiyama coupling

Stille reaction

Suzuki reaction

Sonogashira coupling

Intramolecular Heck reaction

The reaction was described in 1963 by chemists Castro and Stephens.[1][2] The reaction is similar to the much older Rosenmund–von Braun synthesis (1914)[3][4] between aryl halides and copper(I) cyanide and was itself modified in 1975 with as the Sonogashira coupling by adding a palladium catalyst and preparing the organocopper compound in situ, allowing copper to also be used catalytically.[5][6]

A typical reaction diphenylacetylene is obtained by the coupling of iodobenzene with CuC2C6H5 in hot pyridine:[1]

Unlike the Sonogashira coupling, the Castro–Stephens coupling can produce heterocyclic compounds when a nucleophilic group is ortho to the aryl halide, although this typically requires use of dimethylformamide (DMF) as solvent.[7][8]

Cross-coupling reactionsCross-coupling reactions

In one important reaction type, a main group organometallic compound of the type R-M (R = organic fragment, M = main group center) reacts with an organic halide of the type R'-X with formation of a new carbon-carbon bond in the product R-R'. The most common type of coupling reaction is the cross coupling reaction.[1][2][3]

Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed cross coupling reactions.[4][5]

Broadly speaking, two types of coupling reactions are recognized:

Heterocouplings combine two different partners, such as in the Heck reaction of an alkene (RC=CH) and an alkyl halide (R'-X) to give a substituted alkene, or the Corey–House synthesis of an alkane by the reaction of a lithium diorganylcuprate (R2CuLi) with an organyl (pseudo)halide (R'X). Heterocouplings are also called cross-couplings.

Homocouplings couple two identical partners, as in the Glaser coupling of two acetylides (RC≡CH) to form a dialkyne (RC≡C-C≡CR).

Coupling reactions are illustrated by the famous Ullmann reaction:

An illustrative cross-coupling reaction is the Heck coupling of an alkene and an aryl halide: